Interpreting the molecular mechanisms of disease variants in human transmembrane proteins

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. To accurately predict variant consequences, one fundamentally needs to understand the reasons for pathogenicity. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. Membrane proteins though are widely understudied. We here interpret for the first time on a larger scale variant effects by performing structure-based estimations of changes in thermodynamic stability under the usage of a membrane-specific force-field and evolutionary conservation analyses of 15 transmembrane proteins. We find evidence for loss of stability being the cause of pathogenicity in more than half of the 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.