The variants associated with maintained channel function but dampened ciliary localization, including PC2 W414G (mouse PC2 W412G) (Cai et al, 2014) and PC2lrm4 (mouse PC2 E442G) (Walker et al, 2019) with mutations in the TOP domain encoded by the S1–S2 loop, cause polycystic kidney in human and mice, respectively. This evidence concerns the gene PKD2 and polycystic kidney disease.