PPP2R5D encodes the B56δ regulatory subunit of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase that modulates substrate selectivity and catalytic activity 1. This subunit is highly expressed in the brain and plays crucial roles in neuronal development, learning, and memory 1. PP2A opposes growth-promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways, with decreased activity promoting cellular growth 2. The PPP2R5D-PP2A holoenzyme regulates neuronal signaling and maintains neurons through specific substrate dephosphorylation, including modulation of liprin-α1 liquid-liquid phase separation via phosphorylation control 3. Pathogenic de novo missense variants in PPP2R5D cause Houge-Janssens syndrome type 1, characterized by neurodevelopmental delay, macrocephaly, intellectual disability, autism spectrum disorders, epilepsy, and behavioral problems 24. Patient-derived neurons show hyperproliferation and increased neurite outgrowth, suggesting a dominant-negative mechanism rather than loss of function 5. The most common pathogenic variant is E198K, which disrupts pathways critical for neuronal development and synaptic signaling 45. Allele-specific knockdown approaches show therapeutic promise for reversing neuronal defects 5.