TBC1D2B is a GTPase-activating protein (GAP) primarily involved in early endocytic trafficking and autophagy regulation. As a RAB-specific GAP, TBC1D2B functions in multiple membrane trafficking pathways by inactivating RAB7 and RAB7A, thereby preventing premature lysosomal degradation of cargo 12. TBC1D2B colocalizes with RAB5-positive early endosomes and is essential for efficient epidermal growth factor internalization during early endocytosis 3. Beyond its canonical GAP function, TBC1D2B contains a functional LC3-interacting region (LIR) motif and promotes autophagy initiation through binding to LC3/GABARAP and ATG12 conjugation complexes, with the protein undergoing phase separation during autophagy induction 4. TBC1D2B is also recruited to early endosomes by RAB31 and RAB22A to coordinate exosome and microvesicle biogenesis by suppressing multivesicular endosome fusion with lysosomes 12. Clinically, biallelic loss-of-function TBC1D2B variants cause a progressive neurodevelopmental disorder characterized by seizures (80% of cases), gingival overgrowth, cognitive impairment, and abnormal mandible morphology including cherubism-like features 56. Disease progression includes neuronal deterioration, cerebellar atrophy, and evidence suggests defects in autophagy and endolysosomal trafficking underlie neuronal dysfunction 5.