Protein language model rescue mutations highlight variant effects and structure in clinically relevant genes

Despite being self-supervised, protein language models have shown remarkable performance in fundamental biological tasks such as predicting impact of genetic variation on protein structure and function. The effectiveness of these models on diverse set of tasks suggests that they learn meaningful representation of fitness landscape that can be useful for downstream clinical applications. Here, we interrogate the use of these language models in characterizing known pathogenic mutations in medically actionable genes through an exhaustive search of putative compensatory mutations on each variant's genetic background. Systematic analysis of the predicted effects of these compensatory mutations reveal unappreciated structural features of proteins that are missed by other structure predictors like alphafold.