PPP2R1A encodes the PR65 scaffolding subunit of protein phosphatase 2A (PP2A), which coordinates assembly of the catalytic subunit with variable regulatory B subunits to form functional PP2A complexes 1. As a critical component of PP2A, PPP2R1A opposes serine/threonine protein kinases, including growth-promoting kinases in the PIK3CA/AKT/mTOR and RAS/MAPK pathways 1. The protein functions in multiple cellular processes including chromosome 19, transcriptional regulation as part of the Integrator-PP2A complex, and participation in STRIPAK complexes that regulate various signaling pathways 1. PPP2R1A mutations are associated with Houge-Janssens syndrome type 2, characterized by neurodevelopmental delay, hypotonia, seizures, and behavioral problems 1. Cancer-associated mutations, particularly the recurrent p.R183 hotspot mutation, occur in endometrial cancers and ovarian clear cell carcinomas 2 3. These mutations can occur in benign endometriotic lesions without malignant transformation 4. Importantly, PPP2R1A mutations enhance sensitivity to immunotherapy and ATR inhibitors, suggesting potential therapeutic targets 5 3. The mutations appear to disrupt normal PP2A function, leading to altered cellular signaling and therapeutic vulnerabilities.