NPRL2 is a core component of the GATOR1 complex, a negative regulator of mTORC1 signaling that functions as a tumor suppressor 1. NPRL2 displays GTPase-activating protein (GAP) activity toward Rag GTPases, inactivating them under amino acid-deficient conditions to suppress mTORC1 pathway activation 1. In cancer cells with NPRL2 inactivation, mTORC1 becomes hyperactive and insensitive to amino acid starvation 1. Pathogenic NPRL2 variants cause familial focal epilepsy with variable foci, manifesting primarily as focal seizures (70% of cases), often sleep-related and drug-resistant 23. Loss-of-function variants predominate (approximately 67% of epilepsy-related GATOR1 variants), with focal cortical dysplasia present in ~20% of cases 43. Mean seizure onset occurs at 4.4 years, with sudden unexpected death in epilepsy (SUDEP) occurring in ~10% of families 4. Clinically, NPRL2 loss accelerates c-MYC-driven lymphoma development and renders tumors sensitive to mTOR inhibitors 5. NPRL2 restoration in non-small cell lung cancer activates CD8+ T cell-mediated antitumor immunity through downregulation of mTOR signaling and immunosuppressive molecules 6. These findings establish NPRL2 as a critical regulator linking metabolic sensing to both neuronal excitability and immune-mediated tumor control.