Changelog

PVS1: G2P molecular mechanism integration. DECIPHER Gene2Phenotype (G2P) database now provides primary GoF/DN guard for PVS1. gof_genes_g2p view contains 198 pure GoF/DN monoallelic genes where PVS1 is blocked.

PVS1: GOF_AD_GENES reduced from 36 to 14 fallback genes (genes not in G2P: 6 neurodegeneration/toxic aggregation, 3 somatic/neomorphic, 5 absent from G2P 2026-02-28 release). PRSS1 added to fallback.

PVS1: GNAS removed from GOF_AD_GENES (dual-mechanism: McCune-Albright = GoF, pseudohypoparathyroidism 1A = LoF). GNAS LoF variants now correctly receive PVS1.

PVS1: 49 dual-mechanism genes (SCN5A, LMNA, KCNH2, KCNQ1, FGFR1) excluded from GoF view, preserving PVS1 for legitimate LoF phenotypes.

PVS1: G2P confidence filter: only definitive, strong, moderate included. Limited confidence excluded.

Subtractive change: can only remove PVS1 from GoF/DN genes. Cannot create false P/LP.

Clinical trigger: PD2025_090 PRSS1 p.Gly177Ter (stop_gained in GoF gene).

DECIPHER G2P: Molecular mechanism data (g2p_gene_mechanism table, 2,372 records) added to reference_db alongside existing HPO enrichment data.

gof_genes_g2p view: 198 pure GoF/DN monoallelic genes for PVS1 guard. Dual-mechanism genes excluded.

New loader script: scripts/load_g2p_mechanism.py with dry-run, force flags, and 9-point validation.

PVS1: GoF AD gene exclusion (HELIX-CR-2026-022). GOF_AD_GENES curated list (36 genes) blocks PVS1 for AD genes where disease mechanism is gain-of-function, dominant-negative, or toxic aggregation.

PVS1: ClinGen AD Definitive/Strong genes bypass pLI/LOEUF constraint gate (v3.16.6). Genes like TUBB1 with ClinGen AD Definitive now qualify for PVS1.

LP classification: Disease association gate for LP rules LP4, LP5, LP6 (v3.16.7, HELIX-CR-2026-021). Prevents LP in genes without known Mendelian disease mechanism.

ClinGen Gene-Disease Validity integration (v3.16.0): ar_lof_genes_clingen and disease_associated_genes_clingen reference tables replace Python constants.

Clinical triggers: PD2025_082 RAC1 frameshift (GoF gene), PD2025_090 discordance analysis.

ClinGen Gene-Disease Validity: ar_lof_genes_clingen and disease_associated_genes_clingen tables added to reference_db.

Total reference databases: 14 (previously 13).

PM1: Critical functional domains migrated from Python constant to reference database table (refdb.interpro_pfam_domains). HELIX-CR-2026-012.

PM1: Full InterPro Pfam catalog (27,481 entries) loaded. 49 domains marked critical across 14 categories.

PM1: CRITICAL_PFAM_DOMAINS converted from short names to InterPro-verified accession numbers (v3.14.0, HELIX-CR-2026-011). Fixed 0 legitimate PM1 applications since curated list introduction.

PM1: Post-fix validation on HG2023_206: PM1 count from 2 (false positive) to 1,139 (legitimate).

PVS1: ClinVar LOF evidence as fifth constraint gate path (v3.13.0, HELIX-CR-2026-010). Small AD genes with ClinVar P/LP LOF but uninformative gnomAD constraint now qualify.

PP3/BP4: Missense consequence guard (v3.12.1, HELIX-CR-2026-009). BayesDel path now requires missense_variant consequence.

Clinical triggers: HG2023_206 RYR1 (PM1 fix), GCM2 p.Arg131Ter (PVS1 + PP3 guard).

InterPro / Pfam added as 13th reference database (27,481 Pfam entries).

Loader script: scripts/load_interpro_pfam.py with InterPro API fetch and offline fallback.

Total reference databases: 13 (previously 12).

Multi-Source HPO Enrichment Pipeline: gene-phenotype annotations expanded from 1 source (5,173 genes) to 6 sources (5,688 genes, +10%)

HPO Consortium: 320K records, 5,173 genes (primary source, curated gene-phenotype associations)

Orphanet disease-to-HPO: 168K records, 3,176 genes with clinical frequency data (via Orphadata en_product4.xml + en_product6.xml)

DECIPHER Gene2Phenotype (G2P): 43K records, 2,125 genes from 7 clinical panels (DD, Eye, Cardiac, Skin, Skeletal, Cancer, Ear)

Monarch Initiative: 151K records, 4,791 genes (HPO Consortium redistribution via Monarch KG)

ClinVar-MedGen: 245K records, 5,258 genes (P/LP variant -> MedGen CUI -> HPO chain mapping, largest contributor of new genes)

Manual clinical curation: common-disease genes outside rare-disease HPO scope (TBC1D4 with PMID evidence)

3,292 genes with increased HPO term coverage from cross-source aggregation

Source priority ordering: Orphanet > G2P > HPO Consortium > Monarch > ClinVar-MedGen

Low-confidence filtering: Orphanet modifying/candidate and G2P limited entries excluded from clinical view

Classifier version bumped to v3.12.0

PP4 criterion evaluates against enriched HPO set (more genes trigger PP4)

No ACMG criteria logic changes -- only annotation data expanded

DECIPHER G2P added as new reference database (7 clinical panels)

Monarch Initiative added as new reference database

MedGen HPO-OMIM mapping added as new reference database

HPO database entry updated to reflect multi-source enriched view

Total reference databases: 12 (previously 9)

PVS1 disease association gate: requires established disease association before applying PVS1 (ClinVar P/LP, Orphanet, ClinGen HI, AR LoF list, or VCEP coverage)

BS1 constraint-implied AD fallback: uses AD threshold (0.1%) for LoF-constrained genes without inheritance data

BS1 cascade expanded from 5 to 8 levels with explicit Orphanet AR and AR_LOF_GENES priorities

PVS1 non-canonical splice exclusion: splice_donor_5th_base_variant, splice_donor_region_variant, splice_acceptor_5th_base_variant blocked from PVS1 (v3.11.4)

PVS1 NMD_transcript_variant exclusion fix: NMD_transcript no longer blocks PVS1, NMD_escaping_variant now blocks instead (v3.11.3)

De novo projection: prospective PS2 upgrade computation for VUS variants to guide trio testing (v3.11.0)

ClinVar low-confidence disease association gate: 1-star P/LP requires gene disease evidence (v3.10.0)

disease_genes_clinvar CTE circular reference fix: review_stars >= 2 filter (v3.10.1)

PVS1 last-exon NMD downgrade: last-exon truncating variants receive PVS1_Strong instead of PVS1 Very Strong (v3.9.0)

BP1 ClinVar pathogenic missense guard and PP3_Supporting label (v3.8.2)

PP3_Strong disease association gate (v3.8.1)

Orphanet/Orphadata documented as separate reference database (gene-disease-inheritance for 3,200 genes)

VCEP gene-specific specifications documented as separate reference database (~50-60 genes)

Total reference databases: 9 (previously 7)

ACMG/AMP 2015 classification with Bayesian point-based framework (Tavtigian 2018/2020)

19 of 28 ACMG criteria automated

BayesDel_noAF with ClinGen SVI-calibrated thresholds for PP3/BP4 (Pejaver 2022)

SpliceAI integration for PP3_splice with PVS1 double-counting prevention

ClinVar override logic with review star quality filtering

Gene-specific VCEP threshold support

gnomAD v4.1 (759M variants, 807K individuals)

gnomAD Constraint v4.1 (18.2K genes)

ClinVar 2025-01

dbNSFP 4.9c

SpliceAI precomputed (Ensembl MANE Release 113)

HPO gene-phenotype associations

ClinGen dosage sensitivity

Ensembl VEP Release 113 with local offline cache

Lin semantic similarity with HPO ontology graph

Five-tier clinical priority system

Gene-level deduplication and aggregation

Automatic HPO term extraction from free-text clinical descriptions

Seven-component scoring algorithm (constraint, deleteriousness, phenotype, dosage, consequence, compound het, age relevance)

Six screening modes (diagnostic, neonatal, pediatric, proactive adult, carrier, pharmacogenomics)

Age-aware prioritization with curated gene lists

Clinical boosts for ethnicity, family history, sex-linked inheritance, consanguinity, pregnancy

Four-tier priority ranking with clinical actionability labels

Conversational variant analysis with natural language database queries

Biomedical literature search (1M+ publications, local PubMed mirror)

Four-level adaptive clinical interpretation generation

PDF and DOCX report export with Helena branding

Genomics-aware visualization suggestions

On-premise LLM inference within EU infrastructure

EU-based processing (Helsinki, Finland)

All databases stored and queried locally

Zero external API calls during variant processing

GDPR-compliant data handling

DuckDB-based analytical pipeline