UNC80 is an essential auxiliary subunit of the NALCN sodium leak channel complex that regulates neuronal resting membrane potential and excitability 1. As a massive HEAT-repeat protein, UNC80 forms an intertwined anti-parallel superhelical assembly with UNC79, which docks onto the NALCN-FAM155A pore-forming subcomplex 1. The C-terminal domain of UNC80 contains an inter-subunit interaction domain with UNC79 that is critical for dendritic localization of the complex 2. UNC80 is essential for NALCN sensitivity to extracellular calcium and neuropeptide regulation of sodium-leak currents [UniProt annotation]. Biallelic loss-of-function UNC80 variants cause infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2), characterized by severe neurodevelopmental delay, failure to thrive, central sleep apnea, and often refractory epilepsy 3. Disease-associated UNC80 mutations impair dendritic localization while maintaining whole-cell currents, disrupting critical regulation of dendritic membrane potential 2. Additional clinical features include severe gastrointestinal dysfunction and progressive developmental regression 4. The NALCN channelosome containing UNC80 originated in early eukaryotes and is essential in rodent development 5. These findings establish UNC80 as a critical determinant of neuronal excitability and a major genetic cause of neurodevelopmental disease.