SNAP2 performs best for the ALL data set. This figure shows performance estimates for the ALL data set. Our new method SNAP2 (dark blue, AUC = 0.905) outperforms its predecessor SNAP (light blue, AUC = 0.880), PolyPhen-2 (orange, AUC = 0.853) and SIFT (green, AUC = 0.838) over the entire spectrum of the Receiver Operating Characteristic (ROC) curve. Curves are significantly different from each other at a significance level of P < 10-4 as measured by the DeLong method . All SNAP2 results were computed on the test sets not used in training after a rigorous split into training, cross-training and testing. Results for PolyPhen-2 and our original SNAP included some of those proteins in their training, suggesting over-estimated performance.