PKD2 encodes polycystin-2, a nonselective cation channel that functions as a homotetrameric ion channel or heteromerizes with PKD1 to form a complex with altered selectivity properties. In the primary cilium, PKD2 acts as a cation channel preferring monovalent over divalent cations, facilitating K⁺, Na⁺, and Ca²⁺ influx with low Ca²⁺ selectivity, whereas the PKD1-PKD2 heterocomplex displays higher Ca²⁺ permeability and functions primarily as a Ca²⁺-permeable channel. PKD2 participates in fluid-flow mechanosensation in renal epithelium and regulates intracellular calcium signaling through interactions with channels including TRPV4, TRPC1, IP3R, and RYR2. Biallelic and monoallelic loss-of-function PKD2 variants cause autosomal dominant polycystic kidney disease (ADPKD), accounting for approximately 15% of ADPKD families, with patients carrying PKD2 mutations showing delayed kidney failure onset (typically mid-70s) compared to PKD1-mutant carriers 1. Among ADPKD patients with confirmed genetic diagnosis, approximately 14% carry PKD2 variants 2, and 100% of patients with loss-of-function PKD2 variants present with ADPKD 2. At the population level, gnomAD v4.1 classifies PKD2 as loss-of-function tolerant (LOEUF=0.68); this population-level constraint is distinct from clinical pathogenicity in ADPKD disease contexts. Tolvaptan represents an approved therapeutic option to slow ADPKD progression 3, and emerging treatments targeting downstream signaling pathways are under investigation.