ARFGEF2 (BIG2 protein) is a guanine nucleotide exchange factor that activates ARF GTPases (primarily ARF1, ARF3, ARF5, and ARF6) by promoting GDP-GTP exchange 1. It functions as a critical regulator of vesicle trafficking, particularly controlling transport from the trans-Golgi network to endosomes and recycling endosomes, while maintaining endosomal compartment integrity 1. ARFGEF2 facilitates membrane association of trafficking complexes (AP-1 and GGA1) and mediates receptor recycling, including transferrin receptor and GABA(A) receptor trafficking 1. Additionally, it functions as an A kinase-anchoring protein linking ARF and PKA signaling pathways 1. Clinically, ARFGEF2 mutations cause autosomal recessive periventricular nodular heterotopia with microcephaly and developmental delay 2. The expanded phenotypic spectrum includes dystonic movement disorders, cardiomyopathy, cerebral atrophy, and putaminal hyperintensity 34. Mechanistically, ARFGEF2 disruption impairs neural progenitor proliferation and neuronal migration during cortical development by disrupting vesicle-mediated transport of adhesion molecules like E-cadherin and β-catenin 1. Murine studies demonstrate ARFGEF2 is essential for early embryonic development, with homozygous null embryos failing at the 4-cell stage 5. Beyond neurological disease, dysregulation of ARFGEF2-derived circular RNA promotes pancreatic cancer lymph node metastasis through JAK2-STAT3 activation 6.