Figure 3

Investigating the effect of ARHGAP19 variants in silico.

(A) Multiple sequence alignment of ARHGAP19 orthologs shows species conservation of identified variants. (B) Predicted WT ARHGAP19 protein structure (UniProt: Q14CB8) using AlphaFold2, colored with the perresidue confidence score (pLDDT). Dark blue, very high confidence (pLDDT > 90); light blue, confident (90 > pLDDT > 70); yellow, low confidence (70 > pLDDT > 50); orange, very low confidence (pLDDT < 50). AlphaFold-generated mutant protein structures (red) derived from the identified frameshift (C) and nonsense (D) variants and aligned to the WT ARHGAP19 protein (green). (E) The effect of identified missense variants on 3D ARHGAP19 structure. WT residues are colored green and mutant residues are colored red. (F) Dot plots showing predicted free energy changes (ΔGMUT – ΔGWT) for missense variants on protein stability. Calculations were performed on variants within the very high confidence regions (pLDDT >90). Data are given as individual data points (green circle), as well as mean (black circle) ± SD (black line).