STON2 (stonin 2) is an adapter protein that functions as a major regulator of clathrin-mediated endocytosis (CME) in synaptic vesicle recycling 1. Mechanistically, STON2 facilitates the recognition and trafficking of synaptic vesicle proteins, particularly through interaction with synaptotagmin 1 (Syt1), a calcium sensor critical for CME 1. Beyond synaptic function, STON2 maintains lysosomal membrane integrity and activates the Akt-mTOR survival axis 2, and regulates immune cell differentiation, specifically Th17 cell populations 3. Clinically, STON2 variants are associated with schizophrenia susceptibility. The C-C (307Pro-851Ala) haplotype increases schizophrenia risk and causes synaptic transmission deficits and schizophrenia-like behaviors in knockin mice 1. The Pro307 allele correlates with altered cortical surface area in schizophrenia patients 4. Importantly, patients carrying this haplotype show preferential response to haloperidol 1, suggesting potential pharmacogenetic applications. ADDITIONAL DISEASE RELEVANCE: STON2 variants associate with keratoconus, a corneal thinning disorder 5. STON2 overexpression promotes oral squamous cell carcinoma and papillary thyroid carcinoma progression 26, while reduced STON2 expression supports ovarian cancer stem cell properties 7, indicating context-dependent oncogenic roles.