Fig. 2: V2R clinical genetics and variant effect predictors.
From: A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR
a, Surface expression scores of V2R variants in gnomAD, ClinVar categories or Human Gene Mutation Database (HGMD) categories. Patho., pathogenic. b, Fraction of each variant category that is poorly, moderately or well expressed. c, Relationship between allele frequency in gnomAD and surface expression score. The dashed line indicates an allele frequency of 0.001, a commonly used threshold for common versus rare variation. d, Although VEPs are quite accurate for predicting pathogenicity, they cannot inform on the molecular mechanism of pathogenicity, highlighting the importance of mechanistic screens. e, Receiver operating characteristic curve for different VEPS, or the empirical surface expression scores, for distinguishing NDI alleles from gnomAD alleles. AUC, area under the curve. f, Correlations between the predictors and the empirical surface expression scores. P < 1 × 10100 in all cases. g, Distance between the endogenous ligand (AVP) and NDI variants with different expression levels. n = 26, 26 and 69 for well expressed, moderately expressed and poorly expressed, respectively. The center value (white circle) of each violin plot is the median; the box limits represent the first and third quartiles; and the whiskers extend to either the most extreme value, or interquartile range × 1.5, whichever is smaller. Mann–Whitney U test, two-sided, P = 1.5 × 10−3 and 7.7 × 10−4 for well and moderately expressed versus poorly expressed. h, NDI variants of different expression levels illustrated on the V2R structure (PDB ID: 7KH0). i, Surface expression of all variants predicted by AlphaMissense to be pathogenic (gray histogram), along with the distribution of all missense variants (black line). P = 2.6 × 10−5. j, Distance between variants with different expression levels to AVP in the solved V2R structure. n = 654, 946 and 977 for well expressed, moderately expressed and poorly expressed, respectively. P = 2.2 × 10−21 for well versus poorly expressed; 0.03 for moderately versus poorly expressed; 1.9 × 10−9 for well versus moderately expressed; Mann–Whitney U test, two-sided. Violin plot features are the same as in g.
