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

The interpretation of missense variants remains a major challenge in clinical genetics. "Meta-domains" aggregate population and pathogenic variation across homologous Pfam domain instances in the human proteome, providing per-residue context for interpreting variants of uncertain significance (VUS). Our 2019 implementation, MetaDome, is widely used and named in clinical variant-classification guidelines. Here we present the MetaDome 2027 update, featuring a comprehensively updated dataset and GRCh38 support. The redesigned pipeline enables incremental updates of GENCODE, UniProtKB/Swiss-Prot, Pfam, gnomAD, and ClinVar while maintaining 100% sequence-identity gene-to-protein mapping. Annotated Pfam domain instances grew 14.9% from 71,419 to 82,069 and meta-domain-eligible Pfam families ([≥]2 human occurrences) by 73.3% from 3,334 to 5,778; Pfam domains are annotated to 92% of human proteins. Approximately 43% of mapped protein-coding nucleotides (14.3 million in GRCh38, 13.8 million in GRCh37) are in a meta-domain; in GRCh38 67.9% (37,692 of 55,548) of pathogenic or likely pathogenic ClinVar missense variants fall at such a position. We show how MetaDome helped reclassify a de novo missense VUS in RALA and identify 52,463 ClinVar missense VUS for which meta-domains supply otherwise unavailable pathogenic evidence. MetaDome is freely available at www.metadome.app.