AbstractMany methodologically diverse computational methods have been applied to the growing challenge of predicting and interpreting the effects of protein variants. As many pathogenic mutations have a perturbing effect on protein stability or intermolecular interactions, one highly interpretable approach is to use protein structural information to model the physical impacts of variants and predict their likely effects on protein stability and interactions. Previous efforts have assessed the accuracy of stability predictors in reproducing thermodynamically accurate values and evaluated their ability to distinguish between known pathogenic and benign mutations. Here, we take an alternate approach, and explore how well stability predictor scores correlate with functional impacts derived from deep mutational scanning (DMS) experiments. In this work, we compare the predictions of 9 protein stability‐based tools against mutant protein fitness values from 49 independent DMS datasets, covering 170,940 unique single amino acid variants. We find that FoldX and Rosetta show the strongest correlations with DMS‐based functional scores, similar to their previous top performance in distinguishing between pathogenic and benign variants. For both methods, performance is considerably improved when considering intermolecular interactions from protein complex structures, when available. Furthermore, using these two predictors, we derive a “Foldetta” consensus score, which improves upon the performance of both, and manages to match dedicated variant effect predictors in reflecting variant functional impacts. Finally, we also highlight that predicted stability effects show consistently higher correlations with certain DMS experimental phenotypes, particularly those based upon protein abundance, and, in certain cases, can significantly outcompete sequence‐based variant effect prediction methodologies for predicting functional scores from DMS experiments.