Nature Genetics - popEVE is a proteome-wide deep generative model to identify and predict pathogenicity of missense mutations causing genetic disorders.

Tenthorey et al. compare the effects of missense and indel mutations on the acquisition of functional novelty by the rapidly evolving antiviral protein TRIM5α. They find that single indel mutations al...

Isoforms are seldom considered in genetic variant interpretation. Here the authors map common and rare variants to alternative isoforms, which can be highly expressed and tissue-specific. A common DPP...

AbstractSummary. AlphaMissense is an AI model from Google DeepMind that predicts the pathogenicity of every possible missense mutation in the human proteom

Borges, González-Blanco, Arigela, et al. report new missense mutations in the PRC1 genes RNF2 and RING1 in individuals with neurodevelopmental disorders. Functional dissection of a deleterious variant...

Author summary DDX3X mutations are associated with neurodevelopmental disorders, including DDX3X syndrome and autism spectrum disorder. DDX3X is an RNA binding protein whose loss of function impairs b...

Large-scale experimental analysis of Human Domainome 1, a library containing more than 500,000 missense mutation variants across more than 500 human protein domains, reveals that 60% of pathogenic mis...

SOD1 variants cause the motor neuron disease amyotrophic lateral sclerosis. Axakova et al. functionally assay ∼86% of all possible SOD1 missense variants, producing a variant-effect map resource that ...

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 measurements with protein language models to annotate functional sites across proteins. Mutational effects on stability are largely conserved in homologous domains, enabling accurate stability prediction across entire p

The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defect...