Figure 5. Large-scale analysis of disease-causing variants and variants observed in the population.

The grey distribution shown in the background of all plots represents the distribution of $\mathrm{\Delta }\mathrm{\Delta }G$ values calculated using RaSP for all single amino acid changes in the 1,366 proteins that we analysed (15 of the 1381 proteins that we calculated $\mathrm{\Delta }\mathrm{\Delta }G$ for did not have variants in ClinVar or gnomAD and were therefore not included in this analysis). Each plot is also labelled with the median $\mathrm{\Delta }\mathrm{\Delta }G$ of the subset analysed as well as a range of $\mathrm{\Delta }\mathrm{\Delta }G$ values that cover 95% of the data in that subset (box plot shows median, quartiles and outliers). The plots only show values between –1 and 7 kcal/mol (for the full range see Figure 5—figure supplement 2). (A) Distribution of RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ values for benign (blue) and pathogenic (tan) variants extracted from the ClinVar database (Landrum et al., 2018). We observe that the median RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ value is significantly higher for pathogenic variants compared to benign variants using bootstrapping. (B) Distribution of RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ values for variants with different allele frequencies (AF) extracted from the gnomAD database Karczewski et al., 2020 in the ranges (i) AF>10^-2 (green), (ii) 10^-2 > AF>10^-4 (orange), and (iii) AF<10^-4 (purple). We observe a gradual shift in the median RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ going from common variants (AF>10^-2) towards rarer ones (AF<10^-4).

Figure 5—figure supplement 1. Histogram of $\mathrm{\Delta }\mathrm{\Delta }G$ values from saturation mutagenesis using RaSP on 1,366 PDB structures corresponding to ∼8.8 million predicted $\mathrm{\Delta }\mathrm{\Delta }G$ values.

Figure 5—figure supplement 2. Large-scale analysis of disease-causing variants and variants observed in the population using the RaSP model.

The grey distribution shown in the background of all plots represents the distribution of $\mathrm{\Delta }\mathrm{\Delta }G$ for all single amino acid changes in the 1366 proteins that we analysed. Each plot is also labelled with the median $\mathrm{\Delta }\mathrm{\Delta }G$ of the subset analysed as well as a range of $\mathrm{\Delta }\mathrm{\Delta }G$ values that cover 95% of the data in that subset (box plot shows median, quartiles and outliers). (A) Distribution of RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ values for benign (blue) and pathogenic (tan) variants extracted from the ClinVar database (Landrum et al., 2018). We observe that the median RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ value is higher for pathogenic variants compared to benign variants. (B) Distribution of RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ values for variants with different allele frequencies (AF) extracted from the gnomAD database Karczewski et al., 2020 in the ranges (i) AF > 10^-2 (green), (ii) 10^-2 > AF > 10^-4 (orange), (iii) AF < 10^-4 (purple). We observe a gradual shift in the median RaSP $\mathrm{\Delta }\mathrm{\Delta }G$ going from common variants (AF> 10^-2) towards rarer ones (AF< 10^-4).

Figure 5—figure supplement 3. Histogram of $\mathrm{\Delta }\mathrm{\Delta }G$ values from saturation mutagenesis using RaSP on predicted structures of the entire human proteome corresponding to ∼300 million predicted $\mathrm{\Delta }\mathrm{\Delta }G$ values predicted from 23,391 protein structures.