MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains.

MetaDome 2027 expands meta-domain coverage in the human proteome, with 82,069 annotated Pfam domain instances and 67.9% of GRCh38 ClinVar pathogenic missense variants mapped to meta-domains.

• Why it matters: Interpreting missense variants is difficult for VUS, and evidence is often fragmented across homologous protein regions. Meta-domains aim to aggregate population and pathogenic signals with per-residue context.
• What they did: The update provides a redesigned, incrementally updatable pipeline with GRCh38 support while preserving 100% sequence-identity gene-to-protein mapping across GENCODE, UniProtKB/Swiss-Prot, Pfam, gnomAD, and ClinVar. It increases meta-domain-eligible Pfam families by 73.3% and annotates Pfam domains to 92% of human proteins.
• The result: In GRCh38, 37,692 of 55,548 pathogenic or likely pathogenic ClinVar missense variants fall at meta-domain positions, and meta-domains enable identification of 52,463 ClinVar missense VUS with otherwise unavailable pathogenic evidence.

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