SZT2 is a scaffolding protein and core component of the KICSTOR complex, which functions as a critical negative regulator of mTORC1 signaling in response to amino acid and glucose availability 1. SZT2 localizes to lysosomal membranes where it recruits and positions the GATOR1 complex, facilitating GATOR1's interaction with RAG GTPases and GATOR2 12. The crescent-shaped SZT2 scaffold contains repetitive tandem units that bind other KICSTOR components; its N-terminal domain specifically interacts with GATOR1 through NPRL3 2. Loss of SZT2 results in constitutive mTORC1 localization and activation to lysosomes, even during nutrient deprivation 1. Beyond mTORC1 regulation, SZT2 interacts with autophagy and ciliogenesis-related proteins, suggesting broader cellular functions 3. Biallelic SZT2 mutations cause Developmental and Epileptic Encephalopathy 18 (DEE18), characterized by early-onset seizures (90% of cases), global developmental delay (95%), macrocephaly, craniofacial malformations, and corpus callosum abnormalities 45. Disease severity correlates with residual SZT2 protein activity, with truncating variants causing more severe phenotypes 5. mTORC1 hyperactivation from defective SZT2-GATOR1 positioning represents the primary pathogenic mechanism 6.