MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains
- 1Stanford University
Abstract
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.
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BibTeX
@misc{wiel2026metadome,
title = {{MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains}},
author = {L. Wiel and F. Ferraro and J. Yu and J. Zhen and D. Nachun and R. Mendez and C. M. Reuter and J. L. Cui and D. E. Bonner and J. N. Carter and S. Marwaha and M. van de Vorst and S. Emami and E. Kravets and M. B. Neu and T. W. van Ham and T. Kleefstra and E. A. Ashley and J. A. Bernstein and S. B. Montgomery and C. Gilissen and M. T. Wheeler},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.26.747388},
url = {https://www.biorxiv.org/content/10.64898/2026.08.26.747388v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains
AU - L. Wiel
AU - F. Ferraro
AU - J. Yu
AU - J. Zhen
AU - D. Nachun
AU - R. Mendez
AU - C. M. Reuter
AU - J. L. Cui
AU - D. E. Bonner
AU - J. N. Carter
AU - S. Marwaha
AU - M. van de Vorst
AU - S. Emami
AU - E. Kravets
AU - M. B. Neu
AU - T. W. van Ham
AU - T. Kleefstra
AU - E. A. Ashley
AU - J. A. Bernstein
AU - S. B. Montgomery
AU - C. Gilissen
AU - M. T. Wheeler
PY - 2026
DA - 2026/08/26
PB - bioRxiv
DO - 10.64898/2026.08.26.747388
UR - https://www.biorxiv.org/content/10.64898/2026.08.26.747388v1
AB - 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.
ER -