StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritize potentially pathogenic genetic variation

Missense mutations that change protein stability are strongly associated with human genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel tool to prioritize variants predicted to cause strong instability in essential proteins. We show that by filtering by Delta Delta G values and then prioritizing by StabilitySort Z-scores, we are able to more accurately discriminate pathogenic, protein-destabilizing mutations from population variation, compared with other mutation effect predictors.

Automated summary

Missense mutations that affect protein stability are closely related to human genetic diseases. With the help of the AlphaFold2 prediction model, it is now possible to easily assess the stability effects of genetic variations on a genome-wide scale. This study presents a novel tool that prioritizes variants predicted to cause significant instability in essential proteins, leading to better discrimination between pathogenic mutations and population variations compared to other prediction methods.