PPP2R3B encodes PR70, a regulatory B subunit of protein phosphatase 2A (PP2A) that modulates substrate selectivity and subcellular localization of the catalytic enzyme 1. Located on the pseudoautosomal region of sex chrX|Y, PPP2R3B functions as a tumor suppressor in melanoma by negatively regulating DNA replication and cell cycle progression through stabilization of the CDC6-CDT1 interaction, which delays origin firing 1. Germline duplications of PPP2R3B predispose individuals to melanocytic nevi and melanoma by inducing a proliferative phenotype mediated through C21orf91, independent of the MITF pathway 2. The gene shows sex-specific expression patterns, with lower expression in males correlating with poor melanoma outcomes, supporting its role as an X-linked tumor suppressor 1. PPP2R3B is expressed during human fetal development at sites of chondrogenesis and in muscle tissues 3. Loss-of-function mutations in zebrafish cause progressive idiopathic scoliosis with reduced bone mineralization and mitochondrial abnormalities 3. The protein interacts with NOD2 in innate immune signaling, with interactions compromised by Crohn's disease-associated NOD2 mutations 4. PPP2R3B represents a therapeutically relevant PP2A subunit class that exhibits synthetic dosage lethality with PLK1 overexpression in multiple cancer types 5.