Accurate proteome-wide missense variant effect prediction with AlphaMissense

Abstract

The vast majority of missense variants observed in the human genome are of unknown clinical significance. We present AlphaMissense, an adaptation of AlphaFold fine-tuned on human and primate variant population frequency databases to predict missense variant pathogenicity. By combining structural context and evolutionary conservation, our model achieves state-of-the-art results across a wide range of genetic and experimental benchmarks, all without explicitly training on such data. The average pathogenicity score of genes is also predictive for their cell essentiality, capable of identifying short essential genes that existing statistical approaches are underpowered to detect. As a resource to the community, we provide a database of predictions for all possible human single amino acid substitutions and classify 89% of missense variants as either likely benign or likely pathogenic.

Authors

Jun Cheng, Guido Novati, Joshua Pan, Clare Bycroft, Akvilė Žemgulytė, Taylor Applebaum, Alexander Pritzel, Elisa Wong, Michal Zielinski, Toby Sargeant, Rosalia Schneider, Andrew Senior, John Jumper, Demis Hassabis, Pushmeet Kohli, Žiga Avsec

Venue

Science