CASR and Hypocalcemia: Thus, for CaSR variants identified in individuals with hyper/hypocalcemia, pathogenicity prediction should never be used in isolation to assign causation, and should be combined with knowledge of disease-causing variants (eg, previously characterized missense variants at the same position/mutational hotspots); in silico modeling, which has become easier with the recent publication of several near full-length CaSR cryo-electron microscopy structures [8]; or preferably functional analysis examining protein expression and CaSR activity [4].