CASR and Hypercalcemia: For example, two of the AP2σ variants, Arg61His and Glu122Gly, were predicted to be deleterious (Figs 2 and 3, Supplementary Material, Table S2), but were instead found to have no effect on CaSR-mediated Ca  i2+ signalling (Supplementary Material, Fig. S3); while another, Met117Ile, which was predicted to be likely deleterious by pathogenicity programs (Supplementary Material, Table S1) but not three-dimensional modelling (Fig. 3) had impaired signalling (Fig. 4) and was associated with hypercalcaemia in the patient (Table 1).