SNAP2 and PolyPhen-2 are best for difficult human variants. Bars mark the two-state accuracy (Q2; Eqn. 4) at the default thresholds for SNAP2 (dark blue), SNAP (light blue), SIFT (green), and PolyPhen-2 (orange). Random prediction performance assuming 60:40 effect:neutral background are given in pink. Analysis is based on 3,963 'difficult' cases (2,589 effect; 1,374 neutral) from PMD_HUMAN set. Difficult cases were defined as variants where any of the above method's predictions disagreed; i.e. cases where not all methods, excluding random, gave the same prediction.