allelix 2.3.0__tar.gz → 2.4.0__tar.gz

{allelix-2.3.0 → allelix-2.4.0}/PKG-INFO

@@ -1,6 +1,6 @@
 Metadata-Version: 2.4
 Name: allelix
-Version: 2.3.0
+Version: 2.4.0
 Summary: Open-source genotype analysis toolkit. Format-agnostic ingestion, database-agnostic annotation, offline-first.
 Author: Allelix
 Maintainer-email: dial481 <dial481@users.noreply.github.com>
@@ -55,7 +55,7 @@ Dynamic: license-file
 
 # Allelix
 
-> **Status:** Production. Eight parser formats (including VCF + gVCF), four annotators (ClinVar + ClinPGx + GWAS Catalog + SNPedia), three enrichment sources (gnomAD + AlphaMissense + CADD), licensable-source gating for commercial users, dual-build ClinVar caches (GRCh37 + GRCh38), HTML/JSON/terminal reports and annotated VCF output for pipeline integration (v2.3.0+), methylation + pharmacogenomics focused commands, report diffing, persistent config with commercial-mode safety switch. Build auto-detection from position data (ADR-0021). No regex on prose anywhere in production. The [Changelog](https://github.com/allelix/allelix/blob/main/CHANGELOG.md) tracks every release.
+> **Status:** Production. Nine parser formats (including VCF + gVCF), four annotators (ClinVar + ClinPGx + GWAS Catalog + SNPedia), three GRCh38 enrichment sources (gnomAD + AlphaMissense + CADD) reached from GRCh37 input through a cross-build rsID identity table, licensable-source gating for commercial users, dual-build ClinVar caches (GRCh37 + GRCh38), HTML/JSON/terminal reports and annotated VCF output for pipeline integration (v2.3.0+), methylation + pharmacogenomics focused commands, report diffing, persistent config with commercial-mode safety switch. Modern-build position detection requires at least three concordant seed SNPs and an 80% winning ratio before it overrides a fallback or header signal; a tentative GRCh36 signal instead fails closed to GRCh36 because no modern position cache is safe for it (ADR-0025, ADR-0037). No regex on prose anywhere in production. The [Changelog](https://github.com/allelix/allelix/blob/main/CHANGELOG.md) tracks every release.
 
 ## Quickstart
 
@@ -64,9 +64,10 @@ Dynamic: license-file
 ```bash
 pip install allelix
 
-# Download reference databases (~16 GB default install; ~22 GB if you opt into CADD).
+# Download reference databases (~18 GB default install; ~24 GB if you opt into CADD).
 # Use --no-gnomad / --no-alphamissense to skip the large ones.
-# CADD is opt-in: allelix db update --cadd
+# CADD is opt-in: download with `allelix db update --cadd`, then pass
+# `--cadd` to an analysis or set `sources.cadd = true` persistently.
 allelix db update
 
 # Analyze a genotype file
@@ -78,11 +79,16 @@ allelix analyze your_wgs.vcf.gz --output report.html
 # Multi-sample VCF — pick which sample to analyze
 allelix analyze trio.vcf.gz --sample HG002 --output report.html
 
+# VCF quality gate: rows the variant caller filtered (FILTER not PASS) are
+# skipped and counted; calls with GQ below 20 or no reads become no-calls.
+allelix analyze your_wgs.vcf.gz --keep-filtered --min-gq 10 --output report.html
+
 # Filter to a custom panel (rsIDs + gene names, one per line; '#' comments and blank lines ignored)
 allelix analyze your_genotype_file.txt --filter-file my_panel.txt --output report.html
 
 # Annotated VCF output — VCF-in / VCF-out for pipeline integration
 # Writes a valid VCF with annotations as INFO fields + full provenance in the header.
+# Missing ##contig declarations are synthesized; raw CHROM names are preserved.
 # Refuses to overwrite; requires VCF or gVCF input.
 allelix analyze your_wgs.vcf.gz --vcf-out annotated.vcf
 ```
@@ -93,15 +99,15 @@ See [Development](#development) for source installs and running tests, [Managing
 
 | Format | Status | Notes |
 |---|---|---|
-| MyHappyGenes (Tempus) | ✓ | Tab-delimited, 5 columns. **Build is auto-detected** — real-world MHG exports mislabel the header as "build 37.1" while shipping GRCh38 coordinates. Allelix detects from position data and warns on header/data disagreement (ADR-0021). |
+| MyHappyGenes (Tempus) | ✓ | Tab-delimited, 5 columns. **Build is auto-detected** — real-world MHG exports mislabel the header as "build 37.1" while shipping GRCh38 coordinates. Allelix detects from position data and warns on header/data disagreement (ADR-0021). See [docs/formats.md](https://github.com/allelix/allelix/blob/main/docs/formats.md#myhappygenes-tempus). |
 | 23andMe | ✓ | Tab-delimited, 4 columns, concatenated genotype. Supports build 36/37/38 from header. I-prefixed probe IDs passed through. |
 | AncestryDNA | ✓ | Tab-delimited, 5 columns. Chromosome mapping: 23→X, 24→Y, 25→X (PAR), 26→MT. V1 and V2 chip layouts. |
 | Family Tree DNA | ✓ | CSV, double-quoted fields, concatenated genotype. Build 37 default. |
-| MyHeritage DNA | ✓ | CSV, same structure as FTDNA. Detected by "MyHeritage" in comment header. Handles double-double-quoted field variant. |
+| MyHeritage DNA | ✓ | CSV, same structure as FTDNA. Detected by "MyHeritage" in the file's preamble. Handles double-double-quoted fields and files re-saved through a spreadsheet (padded rows, signature not on line 1, tab-delimited copies). Two exports: the **array** export (pre-2026 kits) and the **low-pass WGS** export (kits from January 2026; genotypes imputed from about 2x coverage), which the report labels as imputed and whose `##reference=build37` line is used as the header build. See [docs/formats.md](https://github.com/allelix/allelix/blob/main/docs/formats.md#myheritage). |
 | Living DNA | ✓ | Tab-delimited despite `.csv` extension. Handles AX-, AFFX-prefixed and CHR:POS positional SNP IDs. |
 | FTDNA Illumina raw | ✓ | Tab-delimited variant of the FTDNA export (distinct from the CSV format above). `RSID/CHROMOSOME/POSITION/RESULT` columns. Build 37 default. |
 | FTDNA FamFinder | ✓ | Third FTDNA file shape: tab-delimited with **separate `ALLELE1` / `ALLELE2` columns** instead of a concatenated `RESULT`. Detected by the `famfinder` substring in the file header plus the 5-column canonical header. Build 37 default. |
-| VCF / gVCF | ✓ | REF/ALT encoding, `0/1` genotype notation. Plain VCF: absence at a position means reference. gVCF: explicit reference blocks (lines with `<NON_REF>` ALT and `END=` INFO) are skipped — they match nothing in any annotation database. Multi-sample files require `--sample <ID>`. Streams via stdlib; `.vcf.gz` handled transparently. Optional `pip install allelix[vcf-index]` enables pysam-backed tabix random access for fast `extract --snps` on huge VCFs. |
+| VCF / gVCF | ✓ | REF/ALT encoding, `0/1` genotype notation. Plain VCF: absence at a position means reference. gVCF: explicit reference blocks (lines with `<NON_REF>` ALT and `END=` INFO) are not annotated — they match nothing in any annotation database — but they are read at high-value positions: a block with low genotype quality or no reads there makes the position a no-call, and so does a gVCF position no record covers. High-value no-calls list the reason (for example `low_gq_block`, `no_coverage`, `filtered`, `low_gq_call`). A plain VCF has no reference blocks, so a position without a record is reported as unknown rather than as reference or as a no-call. Multi-sample files require `--sample <ID>`. Rows the variant caller rejected (FILTER other than `PASS` or `.`) are skipped and counted in the report; `--keep-filtered` keeps them. A call with genotype quality below `--min-gq` (default 20) or with no reads (DP 0) is reported as a no-call. The spanning-deletion allele `*` is treated as symbolic. A VCF that holds only structural-variant or copy-number records (such as a provider's separate `sv` / `cnv` file) is rejected with a message naming the file to use instead; see [docs/formats.md](https://github.com/allelix/allelix/blob/main/docs/formats.md#sequencingcom-30x-whole-genome) for per-provider deliverables. Streams via stdlib; `.vcf.gz` handled transparently. Optional `pip install allelix[vcf-index]` enables pysam-backed tabix random access for fast `extract --snps` on huge VCFs. |
 
 Adding a new format means adding one file to `allelix/parsers/` and registering an instance in the `PARSERS` list in `allelix/parsers/__init__.py`.
 
@@ -110,48 +116,44 @@ Adding a new format means adding one file to `allelix/parsers/` and registering
 | Release | Theme |
 |---|---|
 | **v2.2** | Annotation model expansion (cross-source conflict surfacing, risk-allele display, structured MTAG flag), custom-panel UX improvements, methylation panel retune + citations, ClinVar source switch (VCF → `variant_summary.txt`), CLI cleanups (`db clean` / `db path`). |
-| **v2.3** | Per-source magnitude decomposition, Good / Bad / Neutral annotation repute, JSON v3 (AI-legible output contract), plausibility flagging via zygosity × gnomAD MAF, ClinVar review-status weighting, functional-medicine +/− notation. |
-| **v2.4** | ACMG/AMP automated classification engine, variant consequence annotation (VEP-equivalent). |
-| **v2.5+** | CNVs and repeat-expansion support, dbSNP resolution for rsID-less VCFs, gnomAD genomes (non-coding population frequencies), supplemental genotype file merging. |
-| **v3.0** | Ancestry estimation (PCA + 1KG/HGDP reference panels), Polygenic Risk Score (PRS) integration. |
+| **v2.3** | Annotated VCF output plus v2.3.1 correctness hardening: cross-build enrichment guards, GWAS effect-type disambiguation, conservative build confidence, SNPedia orientation handling, and strict slow-suite drift verification. |
+| **v2.4** | Correctness hardening: cross-build rsID identity table with explicit allele translation, plausibility flag for genotyping-artifact detection, VCF quality gate honouring FILTER and genotype quality, unified rsID-recovery step across all commands, and parser/format hygiene. |
+| **Later** | Variant consequences, CNVs and repeat expansions, gnomAD genomes, supplemental genotype-file merging, ancestry estimation, and PRS support. These are directional themes rather than release commitments. |
 
-Issues and milestones are tracked at [github.com/allelix/allelix/issues](https://github.com/allelix/allelix/issues). Annotator-level strand-aware carrier matching (R-1) shipped in v2.1.0's ADR-0035 cluster.
+Issues and milestones are tracked at [github.com/allelix/allelix/issues](https://github.com/allelix/allelix/issues). Annotator-level strand-aware carrier matching shipped in v2.1.0's ADR-0035 cluster.
 
 ## Supported Databases
 
 | Database | Status | Notes |
 |---|---|---|
-| ClinVar (GRCh37 + GRCh38) | ✓ | Public domain (NCBI). SNVs + indels + multi-allelic sites. **Both builds cached**; `analyze` dispatches by detected build (ADR-0021). Carrier rule (ADR-0007) requires the user to carry the ALT allele. Indel-anchor protection (ADR-0011) prevents single-base array readouts from matching anchor-base indels. |
+| ClinVar (GRCh37 + GRCh38) | ✓ | Public domain (NCBI). SNVs + indels + multi-allelic sites. **Both builds cached**; `analyze` dispatches by detected build (ADR-0021). Rows are matched by chromosome, position, REF and ALT, never by rsID alone, and reference-allele records (REF = ALT) are never reported (ADR-0039). Carrier rule (ADR-0007) requires the user to carry the ALT allele. Indel-anchor protection (ADR-0011) prevents single-base array readouts from matching anchor-base indels. |
 | ClinPGx (formerly PharmGKB) | ✓ | CC BY-SA 4.0. Clinical annotations only — single-rsid SNVs; star alleles and haplotypes deferred (ADR-0009). **Primary non-finding filter is the ClinVar REF carrier rule (ADR-0023):** if ClinVar publishes a single-base REF for the rsid and the user is homozygous for it, the row is suppressed. CPIC's `(rsid, base) → function_class` join (ADR-0020) survives as a secondary tier for rsids ClinVar doesn't catalog. Earlier prose tiers (ADR-0013, ADR-0017, ADR-0018) are superseded. |
 | CPIC (per-allele function table) | ✓ | Internal data source for the ClinPGx filter. Fetched from `api.cpicpgx.org` at `db update` time. Used to populate the `pharmgkb_allele_function` table — not surfaced to end users as its own annotator. |
-| SNPedia | ✓ | CC BY-NC-SA 3.0 US. Pre-built cache downloaded via `db update` (~216K wiki pages, ~105K genotype rows). If the SNPedia database is absent, analysis runs without it. For commercial use, pass `--exclude-snpedia` — `analyze` runs using all other databases and omits SNPedia annotations. The cache can also be rebuilt from source via `scripts/scrape_snpedia.py` + `scripts/parse_snpedia.py`. |
-| GWAS Catalog | ✓ | Public domain (EBI/NHGRI). Trait–SNP associations with p-values and effect sizes. Carrier rule (ADR-0007) requires the user to carry the risk allele. P-value magnitude scoring (ADR-0024) maps continuous p-values to the 0–10 scale; unknown-risk-allele entries fire on rsID match alone but are capped at 3.0. |
-| gnomAD | ✓ | ODbL v1.0. **Enrichment annotator** — adds population allele frequency context to existing annotations. Shows how common each variant is in the general population (~16M exome variants from 730K individuals). A pathogenic variant that 35% of people carry reads very differently from one seen in 0.001%. Pre-built cache downloaded via `db update` (~6GB on disk). Use `--no-gnomad` to skip. |
-| AlphaMissense | ✓ | CC BY 4.0. **Enrichment annotator** — adds DeepMind's protein-structure-based pathogenicity predictions to existing annotations. Scores 71M missense variants on a 0–1 scale: <0.34 = likely benign, >0.564 = likely pathogenic. Complements ClinVar's expert classifications with computational predictions — especially valuable for variants ClinVar hasn't reviewed yet. Pre-built cache downloaded via `db update` (~8GB on disk). Use `--no-alphamissense` to skip. |
-| CADD | ✓ | LicenseRef-CADD (non-commercial). **Enrichment annotator** — adds PHRED-scaled deleteriousness scores from CADD v1.7. **Opt-in**, disabled by default; see [CADD modes](#cadd-modes) below for details. |
+| SNPedia | ✓ | CC BY-NC-SA 3.0 US. Pre-built cache downloaded via `db update` (~216K wiki pages, ~105K genotype rows). The cache carries SNPedia's orientation metadata: minus-strand alleles are complemented before matching, while unknown-orientation palindromic genotypes abstain rather than risk a false match. If the database is absent, analysis runs without it. For commercial use, pass `--exclude-snpedia`. The cache can also be rebuilt from source via `scripts/scrape_snpedia.py` + `scripts/parse_snpedia.py`. |
+| GWAS Catalog | ✓ | Public domain (EBI/NHGRI). Trait–SNP associations with p-values and effect sizes. Carrier rule (ADR-0007) requires the user to carry the risk allele. The reported allele is the study's effect (risk) allele, which can be the reference allele (ADR-0039). P-value magnitude scoring maps continuous p-values to the 0–10 scale; only a confidence-interval field that positively identifies a bare odds ratio receives the odds-ratio modifier. Beta coefficients and ambiguous or unit-bearing effects receive no modifier (ADR-0038). Unknown-risk-allele entries fire on rsID match alone but are capped at 3.0. GWAS risk-allele strand normalization remains deferred. |
+| gnomAD | ✓ | ODbL v1.0. **GRCh38-only enrichment annotator** — adds population allele frequency context to existing annotations. Shows how common each variant is in the general population (~16M exome variants from 730K individuals). A pathogenic variant that 35% of people carry reads very differently from one seen in 0.001%. Pre-built cache downloaded via `db update` (~7 GB on disk). GRCh37 input is enriched only through the rsID identity table's explicit allele translation (ADR-0040); gnomAD's own rsID resolution stays GRCh38-only, and GRCh36 input receives nothing. Use `--no-gnomad` to skip. |
+| AlphaMissense | ✓ | CC BY 4.0. **GRCh38-only enrichment annotator** — adds DeepMind's protein-structure-based pathogenicity predictions to existing annotations. Scores 71M missense variants on a 0–1 scale: <0.34 = likely benign, >0.564 = likely pathogenic. Complements ClinVar's expert classifications with computational predictions — especially valuable for variants ClinVar hasn't reviewed yet. Pre-built cache downloaded via `db update` (~8GB on disk). GRCh37 input is enriched only through the rsID identity table (ADR-0040); GRCh36 input receives nothing. Use `--no-alphamissense` to skip. |
+| CADD | ✓ | LicenseRef-CADD (non-commercial). **GRCh38-only enrichment annotator** — adds PHRED-scaled deleteriousness scores from CADD v1.7. **Opt-in**, disabled by default; GRCh37 input is scored only through the rsID identity table (ADR-0040) and GRCh36 input never; see [CADD modes](#cadd-modes) below for details. |
+| dbSNP rsID identity | ✓ | Public domain (NCBI dbSNP). Not an annotator: a cross-build table of each annotator rsID's GRCh37 and GRCh38 placement and alleles (ADR-0040). Supplies the reference allele for GRCh37 and GRCh38 array data, recovers rsIDs for rsID-less VCFs on both builds, and translates a GRCh37 allele to its GRCh38 coordinates so gnomAD, AlphaMissense and CADD can be looked up. Strand-inverted loci are translated explicitly; palindromic sites (A/T, C/G, or a site whose dbSNP alleles include all four bases) and alleles that became the GRCh38 reference abstain. Pre-built cache downloaded via `db update` (~4.9M rows covering ~3.0M rsIDs, from dbSNP b157). |
 
 ### CADD modes
 
 CADD ranks how deleterious any single-nucleotide variant is using 100+ annotation tracks (coding, non-coding, regulatory). PHRED 10 = top 10% most deleterious, 20 = top 1%, 30 = top 0.1%.
 
-**Opt-in**: enable via `allelix db update --cadd` or `allelix config set sources.cadd true`. Use `--no-cadd` to skip enrichment for a single run.
+**Opt-in**: download the cache with `allelix db update --cadd`. Then pass `--cadd` to an analysis for a one-run override, or enable it persistently with `allelix config set sources.cadd true`. Downloading the cache alone does not change persistent configuration. Use `--no-cadd` to skip enrichment for a single run when it is enabled in config.
 
 Two modes:
 
-- **Cache mode** (default): pre-built ~5.8 GB SQLite cache (~120M variant keys). Covers nearly every position allelix can annotate from its other databases (gnomAD, AlphaMissense, ClinVar). For genotyping chip data (23andMe, AncestryDNA, MyHappyGenes, etc.), this mode is functionally complete — chip probes overwhelmingly target known, cataloged variants.
+- **Cache mode** (default): pre-built ~5.8 GB SQLite cache (~120M GRCh38 variant keys). Covers nearly every GRCh38 position allelix can annotate from its other databases (gnomAD, AlphaMissense, ClinVar). GRCh37 input is scored only after translation through the rsID identity table; GRCh36 input never is.
 - **Full mode** (`options.cadd_full = true`): tabix queries against the complete CADD v1.7 file via pysam (GRCh38 only). Adds coverage for novel or private variants that appear only in WGS/WES data and are not in any pre-computed database. Requires `pip install allelix[cadd]` for the pysam dependency.
 
-If your input is a genotyping chip file, cache mode is all you need.
+If your input is a genotyping chip file, cache mode is normally all you need. GRCh37 chip files are scored through the rsID identity table; GRCh36 files are not scored.
 
 ### Build coverage asymmetry (GRCh37 vs GRCh38)
 
-ClinVar dispatches per-build (ADR-0021) and ships with both GRCh37 and GRCh38 caches. The two caches are essentially equivalent in coverage: 2,896,063 rows / 2,645,206 distinct rsIDs in GRCh37 vs 2,896,102 / 2,645,243 in GRCh38 — a difference of 39 rows.
-
-Despite that equivalence, the same person's WGS file produces noticeably more annotations as GRCh37 than as GRCh38. The mechanism is in the resolution step, not in upstream-data shape. Position-keyed rsID resolution requires exact `(chromosome, position, ref, alt)` alignment between the user's variant call and ClinVar's stored row. Lift-over between builds does not preserve that alignment perfectly: the `~0.4%` of the genome where the reference assembly was rebuilt has different REF alleles, multi-allelic sites split differently, and some benchmark VCF positions drop out entirely in the GRCh38 lift. Each misalignment loses one resolution, which in turn loses all the rsID-keyed downstream annotations that rsID would have driven (ClinVar's own carrier annotation, plus GWAS Catalog, SNPedia, and ClinPGx).
-
-Real GIAB HG002 benchmark, surviving the default `--min-magnitude 5.0` filter: GRCh37 surfaces 520 distinct rsIDs across all sources, GRCh38 surfaces 341. The two sets overlap on 331 rsIDs; 189 are GRCh37-only and 10 are GRCh38-only — pure asymmetric loss in the GRCh38 lift, not different upstream coverage. The unfiltered totals (65,965 vs 4,867) magnify the same pattern at lower magnitudes, mostly via GWAS-Catalog weak-association rows.
+ClinVar dispatches per build and ships with both GRCh37 and GRCh38 caches. gnomAD v4.1 exomes, AlphaMissense, and CADD v1.7 are GRCh38 datasets. Every enrichment lookup is made at GRCh38 coordinates by chromosome, position, reference and alternate allele, never by rsID. For GRCh37 input, the cross-build rsID identity table (ADR-0040) translates the allele the user carries at its GRCh37 position into the matching GRCh38 allele, written explicitly on the GRCh38 forward strand where the reference strand was inverted between assemblies. Palindromic sites (A/T, C/G, or all four bases in dbSNP, whose strand cannot be told from sequence) and alleles that are the GRCh38 reference receive no values rather than a guess. Without the identity table installed, GRCh37 analyses receive no gnomAD, AlphaMissense or CADD values; GRCh36 analyses never do.
 
-If you have a choice of build for the input, GRCh37 surfaces more annotations today on rsID-less VCFs that flow through position-keyed resolution. GRCh38 still surfaces every ClinVar carrier hit it has an exact alignment for.
+Position-based rsID recovery for rsID-less VCFs uses ClinVar (on the selected build), the identity table (on GRCh37 and GRCh38), and gnomAD (GRCh38 only). The same recovery step runs for `analyze`, `stats`, `extract` and `export plink`, so high-value warnings, extracted genotypes and PLINK allele coding all see the recovered rsIDs (ADR-0043). The identity table covers the rsIDs the annotators hold, so an rsID-less GRCh37 VCF now recovers ClinPGx, GWAS Catalog and SNPedia rsIDs as well as ClinVar ones. If you convert between assemblies, re-normalize REF/ALT as part of the conversion and pass `--build` explicitly when the file does not carry a trustworthy build signal.
 
 ### Known ClinPGx limitation: reference-genotype rows where ClinVar and CPIC both lack data
 
@@ -168,9 +170,9 @@ The CFTR × ivacaftor leak (~30+ rows on real data, pre-v0.7.3) is fixed by the
 
 Two ClinVar rows in real-world reports are known upstream artifacts, not Allelix bugs:
 
-- **PKD1 rs199476100 GG (Pathogenic/Likely pathogenic, magnitude 8.5).** This is a stop-gained variant with a gnomAD frequency of 0.0005% (7 observations in 1.38 million chromosomes). Homozygosity for this variant is biologically implausible — PKD1 is autosomal dominant and the nonsense variant would be embryonic-lethal or devastating in homozygous state. The chip genotyping call is almost certainly a probe artifact. The code correctly reports what ClinVar says and what the chip reads; the error is upstream of Allelix. Future work: population-frequency filtering could flag ultra-rare variants where the chip call is likely unreliable.
+- **PKD1 rs199476100 GG (Pathogenic/Likely pathogenic, magnitude 8.5).** This is a stop-gained variant with a gnomAD frequency of 0.0005% (7 observations in 1.38 million chromosomes). Homozygosity for this variant is biologically implausible — PKD1 is autosomal dominant and the nonsense variant would be embryonic-lethal or devastating in homozygous state. The chip genotyping call is almost certainly a probe artifact. The code correctly reports what ClinVar says and what the chip reads; the error is upstream of Allelix. The row is now marked implausible (see [Plausibility flag](#plausibility-flag)) but is still shown.
 
-- **IL10 rs1800896 CT (Pathogenic, magnitude 9.0).** This is a common polymorphism (MAF ~20–40%) in the IL-10 promoter. ClinVar's Pathogenic classification comes from a single submitter for hepatitis C susceptibility; a second submitter classifies the same allele as "Uncertain risk allele" for leprosy susceptibility. The ClinVar VCF aggregates across conditions, so the report may pair the Pathogenic classification with the wrong condition. Future work: ClinVar review-status weighting (number of submitters, star rating) could down-weight single-submitter classifications on common variants.
+- **IL10 rs1800896 CT (Pathogenic, magnitude 9.0).** This is a common polymorphism (MAF ~20–40%) in the IL-10 promoter. ClinVar's Pathogenic classification comes from a single submitter for hepatitis C susceptibility; another submission classifies the allele as "Uncertain risk allele" for leprosy susceptibility. Allelix's per-SCV loader keeps each submitter's significance paired with its own condition, so it does not create cross-submission combinations. The remaining concern is the upstream strength of a single-submitter classification on a common variant. Future work: review-status weighting could down-weight that evidence.
 
 Neither issue affects Allelix's filter logic. Both are inherent to ClinVar's aggregation model and the limitations of array-based genotyping chips.
 
@@ -220,22 +222,41 @@ allelix config set license.commercial true
 
 # Assert that you hold a commercial CADD license
 allelix config set license.cadd true
+
+# Tune the plausibility flag (allele frequencies between 0 and 1)
+allelix config set plausibility.homozygous_max_af 0.0001
+allelix config set plausibility.heterozygous_max_af 0
 ```
 
 CLI flags (`--no-gnomad`, `--no-alphamissense`, `--no-cadd`, `--exclude-snpedia`, `--cadd`) override the config for a single run. The config sets the baseline; flags override per-invocation.
 
+### Plausibility flag
+
+Genotyping arrays sometimes miscall very rare variants, most visibly as a homozygous call for an allele almost nobody carries. Allelix compares each call with the allele's gnomAD frequency and marks it for review. The row is never hidden (ADR-0041).
+
+| Call | gnomAD frequency of the allele | Flag |
+|---|---|---|
+| Homozygous | below `plausibility.homozygous_max_af` (default 0.0001, i.e. 0.01%) | **implausible**: often a genotyping artifact |
+| Heterozygous | at or below `plausibility.heterozygous_max_af` (default 0: gnomAD has the site but no carriers) | **suspicious** |
+| Either | otherwise | plausible |
+
+The HTML report shows a ⚠ icon next to a flagged genotype, with the reason on hover and in the detail panel. The terminal table marks implausible calls with ⚠ and suspicious ones with ?. JSON reports carry `plausibility` on every annotation (`plausible`, `suspicious`, `implausible`, or empty when not assessed).
+
+A call is not assessed when gnomAD has no frequency for the allele. Allelix's gnomAD cache covers exome sites with an rsID, so a missing value says nothing about rarity. Calls are also not assessed when the gnomAD database is skipped. Homozygous calls on X are not assessed because a male's single X reads as homozygous; heterozygous X calls are. Y and mitochondrial calls are not assessed. Confirm a flagged call with a clinical-grade test before relying on it.
+
 ### Database sizes and download times
 
 Not all databases are equal in size. `allelix db update` downloads them all by default, but you can skip the large ones if disk space or bandwidth is a concern:
 
 | Database | On disk | Download time | What it adds |
 |---|---|---|---|
-| ClinVar (GRCh37 + GRCh38) | ~900MB | 1–2 min | Core clinical variant classifications. Required. |
+| ClinVar (GRCh37 + GRCh38) | ~1.6 GB | 1–2 min | Core clinical variant classifications. Required. |
 | ClinPGx + CPIC | ~6MB | seconds | Drug-gene interactions. |
-| GWAS Catalog | ~200MB | 1–2 min | Trait-SNP associations from genome-wide studies. |
-| gnomAD | ~6GB | 5–15 min | Population allele frequencies (how common is this variant?). |
+| GWAS Catalog | ~950 MB | 1–2 min | Trait-SNP associations from genome-wide studies. |
+| gnomAD | ~7 GB | 5–15 min | Population allele frequencies (how common is this variant?). |
 | AlphaMissense | ~8GB | 5–15 min | Missense pathogenicity predictions (how likely to break protein function?). |
-| CADD (opt-in) | ~5GB | 5–15 min | Variant deleteriousness scores (how damaging is this variant?). Enable with `--cadd`. |
+| dbSNP rsID identity | ~460 MB | ~1 min | Cross-build placements: reference allele for array data, rsID recovery on both builds, GRCh37 enrichment translation. |
+| CADD (opt-in) | ~6 GB | 5–15 min | Variant deleteriousness scores (how damaging is this variant?). Download with `db update --cadd`; enable per analysis or in config. |
 
 gnomAD and AlphaMissense are the largest but add the most interpretive context. gnomAD answers "is this variant rare or common?" — a pathogenic variant carried by 35% of the population reads very differently from one seen in 3 people. AlphaMissense answers "does this missense change likely damage the protein?" — especially valuable for the thousands of variants ClinVar hasn't reviewed yet.
 
@@ -243,25 +264,26 @@ To skip either during download: `allelix db update --no-gnomad --no-alphamissens
 
 ### Managing your data
 
-Allelix stores reference database caches at `~/.local/share/allelix/` (Linux/macOS) or the XDG-equivalent on other platforms. Default install (no CADD) is ~16 GB on disk; with the CADD opt-in it's ~22 GB.
+Allelix stores reference database caches at `~/.local/share/allelix/` (Linux/macOS) or the XDG-equivalent on other platforms. Default install (no CADD) is ~18 GB on disk; with the CADD opt-in it's ~24 GB.
 
 ```
 ~/.local/share/allelix/
 ├── alphamissense.sqlite       ~7.8 GB
-├── gnomad.sqlite              ~6.1 GB
+├── gnomad.sqlite              ~7.1 GB
 ├── cadd.sqlite                ~5.8 GB   (only if you opted into --cadd)
-├── clinvar.GRCh37.sqlite      ~470 MB
-├── clinvar.GRCh38.sqlite      ~480 MB
-├── gwas_catalog_associations.tsv  ~700 MB
-├── snpedia.sqlite             ~390 MB
-├── gwas.sqlite                ~190 MB
-└── pharmgkb.sqlite            ~14 MB
+├── clinvar.GRCh37.sqlite      ~800 MB
+├── clinvar.GRCh38.sqlite      ~800 MB
+├── gwas_catalog_associations.tsv  ~745 MB
+├── rsid_identity.sqlite       ~457 MB
+├── gwas.sqlite                ~202 MB
+├── snpedia.sqlite             ~194 MB
+└── pharmgkb.sqlite            ~6 MB
 ```
 
 **The caches are disposable and re-downloadable.** Everything here was fetched by `allelix db update` and can be re-fetched at any time. There's no per-user state in the cache — your genotype files never enter this directory. Safe to delete to reclaim space (or to force a full refresh if you suspect a cache went stale):
 
 ```bash
-# Reclaim all ~16-22 GB, with size report and confirmation prompt
+# Reclaim all ~18-24 GB, with size report and confirmation prompt
 allelix db clean
 
 # Preserve the CADD cache (avoids re-downloading the slowest one, ~5.8 GB)
@@ -289,14 +311,15 @@ du -sh "$ALLELIX_DATA"
 allelix db path --check
 ```
 
-**The one thing worth backing up: `config.toml`.** It lives separately (XDG config dir, typically `~/.config/allelix/config.toml`) and stores your license assertions (commercial-mode toggle, CADD opt-in confirmation) and per-source enable/disable settings. It's the only non-reproducible state in the install. The caches will rebuild on the next `db update`; `config.toml` won't. `allelix db clean` preserves `config.toml` even when it lives inside the data directory (older installs).
+**The one thing worth backing up: `config.toml`.** It lives inside the resolved data directory (typically `~/.local/share/allelix/config.toml`) and stores your license assertions (commercial-mode toggle, CADD opt-in confirmation) and per-source enable/disable settings. It's the only non-reproducible state in the install. The caches will rebuild on the next `db update`; `config.toml` won't. `allelix db clean` always preserves it.
 
 To fully uninstall allelix and reclaim everything:
 
 ```bash
+ALLELIX_DATA=$(allelix db path)
+allelix db clean --yes                 # reference database caches
+rm -f "$ALLELIX_DATA/config.toml"      # license + source-toggle config
 pip uninstall allelix
-allelix db clean --yes            # reference database caches
-rm -rf ~/.config/allelix/         # license + source-toggle config
 ```
 
 ## Data Sources & Licensing
@@ -310,9 +333,10 @@ Allelix source code is licensed under the **GNU Affero General Public License v3
 | ClinPGx (formerly PharmGKB) | clinpgx.org | CC BY-SA 4.0 | Attribution required |
 | CPIC | cpicpgx.org | CC BY-SA 4.0 | Attribution required. Per-allele function data fetched from `api.cpicpgx.org` at `db update` time; used internally for the ClinPGx non-finding filter (ADR-0020), not surfaced as its own annotator. |
 | SNPedia | snpedia.com | CC BY-NC-SA 3.0 US | Attribution required, **non-commercial only**. Use `--exclude-snpedia` to omit. |
-| gnomAD | gnomad.broadinstitute.org | ODbL v1.0 | Attribution required. Population allele frequencies for context; not a clinical annotator. Use `--no-gnomad` to omit. |
-| AlphaMissense | zenodo.org/records/10813168 | CC BY 4.0 | Attribution required. Cheng et al., Science 2023. Missense variant pathogenicity predictions. Use `--no-alphamissense` to omit. |
-| CADD | cadd.gs.washington.edu | LicenseRef-CADD | Attribution required, **non-commercial by default**. Commercial licenses available from UW CoMotion. Opt-in via `allelix db update --cadd`. Use `--no-cadd` to omit. |
+| gnomAD | gnomad.broadinstitute.org | ODbL v1.0 | Attribution required. GRCh38 population allele frequencies for context (GRCh37 input through the identity table); not a clinical annotator. Use `--no-gnomad` to omit. |
+| AlphaMissense | zenodo.org/records/10813168 | CC BY 4.0 | Attribution required. Cheng et al., Science 2023. GRCh38 missense variant pathogenicity predictions (GRCh37 input through the identity table). Use `--no-alphamissense` to omit. |
+| dbSNP (rsID identity table) | ncbi.nlm.nih.gov/snp | Public domain | No restrictions. Cross-build rsID placements derived from dbSNP; not surfaced as an annotator. |
+| CADD | cadd.gs.washington.edu | LicenseRef-CADD | Attribution required, **non-commercial by default**. Commercial licenses available from UW CoMotion. GRCh38 scores (GRCh37 input through the identity table); download with `allelix db update --cadd`, then enable per analysis with `--cadd` or persistently in config. Use `--no-cadd` to omit. |
 
 **Commercial users:** When `license.commercial = true`, non-commercial sources are gated by a three-state permission model. SNPedia is permanently blocked (no commercial license is available). CADD is blocked by default but can be unlocked — the University of Washington offers commercial licenses at `https://els2.comotion.uw.edu/product/cadd-scores`; after purchasing, assert your license with `allelix config set license.cadd true` to re-enable CADD in commercial mode. All other databases (ClinVar, ClinPGx, GWAS Catalog, gnomAD, AlphaMissense) are compatible with commercial use. `allelix config show` displays the permission state for each source.
 
@@ -341,6 +365,8 @@ Of the 104,806 genotype pages in the archive:
 
 None of these are scraping errors. They are editorial inconsistencies on the source wiki. The annotator handles all of them correctly: incomplete entries are skipped, variant title formats are matched, and no false annotations are produced.
 
+The v2.3.1 cache format also preserves each page's SNPedia orientation. Known minus-strand rows are complemented to forward orientation before genotype matching. For palindromic A/T or C/G genotypes whose orientation is unknown, Allelix abstains because the source data cannot distinguish the strands safely. Re-run `allelix db update` after upgrading so a pre-v2.3.1 SNPedia cache is rebuilt.
+
 ## Troubleshooting
 
 ### `ImportError: cannot import name 'UTC' from 'datetime'`
@@ -349,7 +375,7 @@ You're on Python 3.10 or older. Allelix requires 3.11+. `python --version` to ch
 
 ### `allelix db update` failed partway through
 
-Run it again. The update is idempotent — completed downloads are skipped (signal-matched against the upstream freshness probe), so re-running picks up where it left off. If a specific source keeps failing, you can isolate it: `allelix db update --no-gnomad` (or `--no-alphamissense` etc.) to skip the failing source for now, then retry that source standalone later.
+Run it again. The update is idempotent — completed downloads are skipped (signal-matched against the upstream freshness probe), so re-running picks up where it left off. If a specific optional source keeps failing, use its `--no-*` flag to finish the other sources, then remove the skip flag and re-run the full update later. `--only clinvar` exists for the ClinVar-only CI and recovery path; other sources do not currently have standalone `--only` selectors.
 
 If the failure is a network timeout on the same source repeatedly, the issue is likely on the source's end (HuggingFace / NCBI / EBI / etc. transient outage). Wait an hour and retry.
 
@@ -359,7 +385,7 @@ Almost always a schema or interpreter version bump in a recent allelix release t
 
 ### Build mismatch warning when analyzing a known-good file
 
-Either: (a) the file's header claims one build and the position data is actually a different build (real-world MHG / Tempus exports do this — header says 37, positions are 38; ADR-0021 documents the auto-detection), or (b) the file is a GRCh36-era export (pre-2012), which allelix detects accurately but doesn't ship a ClinVar cache for (see [`docs/grch36-liftover.md`](https://github.com/allelix/allelix/blob/main/docs/grch36-liftover.md) for the external-liftover path).
+Either: (a) the file's header claims one build and the position data confidently indicates another (real-world MHG / Tempus exports do this — header says 37, positions are 38), or (b) the position signal is too small or mixed to be authoritative. Allelix requires at least three concordant seed SNPs and an 80% winning ratio. A VCF record without an rsID counts as a seed when it sits at that seed's position on a build, so variant-caller output with an empty ID column is detected by position too. Weaker GRCh37/38 evidence is reported as tentative and the header or fallback remains effective. A tentative GRCh36 winner is the safety exception: Allelix uses GRCh36 so it cannot accidentally query a modern position cache. Modern position-keyed caches are unavailable for that build (see [`docs/grch36-liftover.md`](https://github.com/allelix/allelix/blob/main/docs/grch36-liftover.md)).
 
 If you trust the file's header more than allelix's detection, force the build: `--build grch37` or `--build grch38`. The build banner in the analyze output will reflect what was actually used.
 
@@ -388,6 +414,12 @@ Notable load-bearing ADRs:
 - **ADR-0007 — Genotype matching requires the user to carry the ALT allele.** Applies to ClinVar.
 - **ADR-0009 — ClinPGx matches the user's exact normalized diploid call.**
 - **ADR-0015 — Mock data generators are the contract.** Fixture shape must mirror real data shape; invariants tested.
+- **ADR-0036 — Annotated VCF output contract.** JSON and annotated VCF schemas evolve independently.
+- **ADR-0037 — Conservative position-based build confidence.** A winning build needs at least three matches and an 80% ratio; weaker signals remain diagnostic only.
+- **ADR-0038 — GWAS effect-modifier disambiguation.** Only positively identified odds ratios receive an effect-size modifier; beta and ambiguous effects abstain.
+- **ADR-0042 — VCF quality gate.** The variant caller's FILTER and genotype quality are honoured, low-quality reference blocks are no-calls, and every exclusion is counted in the report.
+- **ADR-0043 — One rsID-recovery step.** Every command that needs rsIDs recovers them for rsID-less input through the same shared step; build detection votes by position instead.
+- **ADR-0041 — Plausibility flag.** Very rare homozygous calls and heterozygous calls with no gnomAD carriers are flagged for review, never suppressed.
 
 Release history: see [`CHANGELOG.md`](https://github.com/allelix/allelix/blob/main/CHANGELOG.md).