VAC14 is a scaffold protein component of the PIKFYVE complex that regulates phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) synthesis and turnover 1. VAC14 forms a pentameric, star-shaped structure that nucleates complex assembly and coordinates both PIKfyve kinase and FIG4 phosphatase activities to maintain normal phosphoinositide levels 2. The protein plays critical roles in endosomal trafficking and biogenesis of multivesicular bodies. VAC14 oligomerization is essential for complex function; mutations at VAC14-VAC14 interfaces impair PI(3,5)P2 generation, VAC14 localization, and complex assembly 2. Beyond its canonical role, VAC14 expression levels influence susceptibility to Salmonella Typhi infection by regulating plasma membrane cholesterol, suggesting a broader role in cellular lipid homeostasis 3. Compound-heterozygous VAC14 mutations cause childhood-onset striatonigral degeneration characterized by prominent neuronal vacuolation, progressive dystonia, and iron accumulation in basal ganglia 45. Enhanced VAC14 homodimerization represents a potential disease mechanism 4. VAC14 is also required for erythroid differentiation, with mutations contributing to anemia 6. CLCN7 reduction partially compensates for VAC14 deficiency in cellular and animal models, suggesting a therapeutic target 7.