DEPDC5 is a core component of the GATOR1 complex, a critical negative regulator of the mTORC1 pathway's amino acid-sensing branch 1. As part of GATOR1, DEPDC5 mediates direct interactions with Rag GTPases and coordinates their nucleotide loading states by promoting RagA/RagB into GDP-bound (inactive) form while favoring RagC/RagD into GTP-bound (active) state 2. In response to amino acid depletion, GATOR1 exhibits GTPase-activating protein activity that inactivates Rag complexes, releasing mTORC1 from the lysosomal surface and suppressing signaling 1. GATOR2 negatively regulates GATOR1 when amino acids are abundant, providing a nutrient-sensing checkpoint 1. Pathogenic DEPDC5 variants cause predominantly focal epilepsies, including familial focal epilepsy with variable foci and infantile spasms, with ~68% penetrance 3. Loss-of-function mutations trigger excessive mTORC1 activation 4, leading to focal cortical dysplasia, drug-resistant seizures, and increased sudden unexpected death in epilepsy risk 5. Null variants associate with worse prognosis than missense variants 3. Clinically, mTOR inhibitors like rapamycin offer precision therapeutic potential, with lacosamide showing efficacy in some patients 6.