memVar: an integrated resource for interpreting human membrane protein variation in molecular and disease contexts
Year: 2026
Type: preprint
Abstract: Interpreting membrane protein variation requires connecting clinical evidence to the membrane environments and molecular interactions that govern protein functions. Here, we introduce memVar (https://memvar.sunnylab.org), an integrated database of 10,906,688unique single-nucleotide variants from ClinVar, COSMIC, and gnomAD across 7,732 human membrane-associated proteins. memVar reconciles genomic, transcript, and protein coordinates to link variants with membrane topology, bilayer depth, lipid contacts, functional sites, partner-specific interaction interfaces, and variant-effect predictions, alongside disease, tissue-expression and regulatory annotations. Coordinated sequence, structure and variant views retain source provenance and distinguish clinical assertions, experimental observations, and computational predictions. Our analysis reveals that pathogenic/likely pathogenic missense substitutions are enriched in transmembrane segments and predicted protein-protein interaction sites relative to benign/likely benign substitutions, with pooled odds ratios of 2.47 and 6.67, respectively. IntAct-derived interaction loss or decrease was experimentally recorded for 57.9% of pathogenic/likely pathogenic substitutions versus 7.4% of benign/likely benign substitutions. CFTR examples contextualize the established G551D gating defect and prioritize W202R, a variant of uncertain significance, for tests of protein maturation, surface abundance and channel activity. By connecting variant records to specific molecular questions, memVar potentially supports mechanism-oriented investigation and prioritization of functional experiments.
Authors: Yizhou Xu, Siming HUANG, Jingyao Zhao, Jianfeng Sun
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225313810