Identification of pathogenic missense mutations using protein stability predictors

Attempts at using protein structures to identify disease-causing mutations have been dominated by the idea that most pathogenic mutations are disruptive at a structural level. Therefore, computational stability predictors, which assess whether a mutation is likely to be stabilising or destabilising to protein structure, have been commonly used when evaluating new candidate disease variants, despite not having been developed specifically for this purpose. We therefore tested 13 different stability predictors for their ability to discriminate between pathogenic and putatively benign missense variants. We find that one method, FoldX, significantly outperforms all other predictors in the identification of disease variants. Moreover, we demonstrate that employing predicted absolute energy change scores improves performance of nearly all predictors in distinguishing pathogenic from benign variants. Importantly, however, we observe that the utility of computational stability predictors is highly heterogeneous across different proteins, and that they are all inferior to the best performing variant effect predictors for identifying pathogenic mutations. We suggest that this is largely due to alternate molecular mechanisms other than protein destabilisation underlying many pathogenic mutations. Thus, better ways of incorporating protein structural information and molecular mechanisms into computational variant effect predictors will be required for improved disease variant prioritisation.