Fig. 3: Gain-of-function and dominant-negative mutations are milder than loss-of-function mutations. | Nature Communications

Fig. 3: Gain-of-function and dominant-negative mutations are milder than loss-of-function mutations.

From: Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure

Fig. 3

a Comparison of predicted | ΔΔG | values for gnomAD variants and pathogenic ClinVar mutations from AD genes classified as dominant negative (DN), gain of function (GOF) and haploinsufficient (HI), and pathogenic ClinVar mutations from AR genes. Boxes denote data within 25th and 75th percentiles, and contain median (middle line) and mean (red dot) value notations. Whiskers extend from the box to furthest values within 1.5x the inter-quartile range. Pairwise group comparisons are significant (p < 0.001, two-sided Holm-corrected Dunn’s test) unless specified (n.s., p-values in order from left to right: 0.786, 0.321, 0.075). b Proportions of different types of mutations occurring in protein interiors, surfaces and interfaces. All pairwise proportion comparisons via Chi-square test are significant, with the lowest effect size being noted for HI vs AR (Cramer’s V = 0.04, compared to 0.20 and 0.26 for DN vs. HI, and DN vs. AR, respectively). c AUC values calculated from ROC curves for discriminating between different types of pathogenic ClinVar mutations, and putatively benign gnomAD variants. Only homozygous gnomAD variants were included for the AR analysis. Error bars denote 95% confidence intervals. Source data are provided as a Source Data file.

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