STXBP2 encodes syntaxin binding protein 2, which plays a critical role in intracellular vesicle trafficking and membrane fusion through interactions with SNARE proteins 1. The protein is essential for cytotoxic granule exocytosis in natural killer (NK) cells and CD8+ T cells, regulating immune cell degranulation processes 2. Mutations in STXBP2 cause familial hemophagocytic lymphohistiocytosis type 5 (FHL5), a severe hyperinflammatory syndrome characterized by unremitting fever, cytopenias, hepatosplenomegaly, and multiorgan failure with high mortality 3. STXBP2 defects account for a significant portion of degranulation-related HLH cases, collectively representing >50% of genetic HLH diagnoses 1. The gene is also associated with microvillus inclusion disease, a fatal congenital diarrheal disorder, where STXBP2 functions alongside MYO5B and STX3 in intestinal epithelial cell trafficking 4. Even heterozygous STXBP2 mutations can predispose to secondary HLH during infections like severe COVID-19, causing impaired NK cell cytolysis and degranulation 2. Rare variants in STXBP2 are enriched in systemic juvenile idiopathic arthritis patients, suggesting broader roles in inflammatory diseases 5.