DENND5A encodes a guanine nucleotide exchange factor (GEF) containing a DENN domain that activates Rab proteins, particularly Rab39 family members, by promoting GDP-to-GTP exchange to facilitate membrane trafficking 1. The protein localizes to the trans-Golgi network and retromer complex, functioning in retrograde transport and endosomal-to-Golgi trafficking 1. DENND5A interacts with apical polarity complex components PALS1 and MUPP1, playing a critical role in symmetric cell division of neural progenitors through centrosomal localization that influences mitotic spindle alignment 23. Loss-of-function variants in DENND5A cause developmental and epileptic encephalopathy 49 (DEE49), characterized by refractory seizures, developmental delay, and cerebral calcifications 42. Disease pathogenesis involves disrupted symmetric division of apical neural progenitors, leading to premature neuronal differentiation and shortened neurogenesis periods 23. Additionally, DENND5A variants impair melanosomal cargo transport through disrupted SNX1 interaction, increasing familial melanoma susceptibility 5. In epithelial cells, DENND5A loss-of-function contributes to aberrant cystogenesis through combined trafficking and mitotic defects 6. Notably, variant type correlates with DEE49 disease severity, with clinical implications for precision medicine approaches 3.