Abstract
Next-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. We here investigate missense variants in membrane proteins — key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. We here perform structure-based estimations of changes in thermodynamic stability and evolutionary conservation analyses of 15 membrane proteins. We find evidence for loss of stability being the cause of pathogenicity in 59% of pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mechanistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.
Competing Interest Statement
The authors have declared no competing interest.