YIPF5 (Yip1 domain family member 5) is a five-span transmembrane protein that plays a critical role in endoplasmic reticulum (ER) to Golgi vesicle-mediated transport 1. In pancreatic beta cells, YIPF5 is essential for transporting proinsulin from the ER to the Golgi apparatus, where it undergoes processing into mature insulin 2. YIPF5 localizes to the ER-Golgi intermediate compartment (ERGIC) and cis-Golgi, recycling between these compartments to maintain Golgi structure 1. Loss of YIPF5 function causes severe ER stress due to proinsulin retention in the ER, leading to beta cell dysfunction and apoptosis 2. Mutations in YIPF5 cause microcephaly, epilepsy, and diabetes syndrome 2 (MEDS2), a congenital disorder presenting with neonatal diabetes (diagnosed within 6 months), severe microcephaly, and seizures 2. YIPF5 is expressed during human brain development and in adult neurons, suggesting its trafficking function is critical for both pancreatic and neuronal cells 2. The pathophysiology involves ER stress-induced disruption of the unfolded protein response, impaired neuronal development, and reduced generation of apical progenitors in the developing cortex 3. YIPF5 represents the first identified gene disrupting ER-to-Golgi trafficking to cause diabetes, establishing a novel disease mechanism 2. Between 2018-2024, YIPF5 joined over 40 known NDM genes, demonstrating genetic heterogeneity in neonatal diabetes etiology 4.