PPP2R2B encodes the Bβ regulatory subunit of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase involved in cell growth control 1. As a regulatory subunit, PPP2R2B modulates PP2A substrate selectivity, catalytic activity, and subcellular localization 1. The protein functions as a tumor suppressor, with reduced expression promoting bladder cancer cell proliferation, migration, and cisplatin resistance 2. PPP2R2B also serves as a nucleocytoplasmic transport molecule, facilitating ISG15 nuclear translocation by mediating ISG15 binding to importin IPO5, which subsequently inhibits DNA repair and activates the STING pathway 2. The gene is critically associated with spinocerebellar ataxia type 12 (SCA12), caused by CAG repeat expansion in PPP2R2B exon 7 1. Normal individuals have 7-28 CAG repeats, while SCA12 patients have 55-78 repeats, leading to increased Bβ expression and bidirectional transcription producing toxic antisense transcripts 3. The expanded repeats show somatic instability across brain regions, with the cerebellum displaying the least instability 4. Genetic variants in PPP2R2B also associate with breast cancer risk and Alzheimer's disease susceptibility 56. Additionally, de novo mutations in PPP2R2B have been identified in patients with intellectual disability 7.