Site-saturation mutagenesis of 500 human protein domains.

ABSTRACT: Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases¹. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins. Using DNA synthesis and cellular selection experiments we quantify the effect of more than 500,000 variants on the abundance of more than 500 human protein domains. This dataset reveals that 60% of pathogenic missense variants reduce protein stability. The contribution of stability to protein fitness varies across proteins and diseases and is particularly important in recessive disorders. We combine stability measurem

SUBMITTER: Beltran A 

PROVIDER: S-EPMC11754108 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature