CLVS2 (clavesin 2) is a neuronal protein required for proper endosomal-lysosomal morphology and organization 1. The protein functions as a phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) binding molecule localized to the trans-Golgi network and clathrin-coated vesicles, where it regulates membrane trafficking and endocytotic processes. CLVS2 plays a critical role in neuronal homeostasis, with genetic variants implicated in neurodegenerative conditions. Missense rare variants in CLVS2 are associated with subjective cognitive decline (SCD), a potential preclinical stage of Alzheimer's disease, with multi-omics evidence suggesting involvement in neurodegeneration pathways 1. A frameshift mutation in CLVS2 was identified exclusively in a schizophrenia case carrying the 22q11.2 deletion, suggesting additional genetic contributions to neuropsychiatric disease 2. Clinically, CLVS2 expression is significantly downregulated in thyroid-associated orbitopathy orbital tissues, correlating with dysregulation of differentiation and oxidative stress pathways 3. The related family member CLVS1 demonstrates functional importance in podocyte endocytosis and oxidative stress regulation, with mutations causing steroid-sensitive nephrotic syndrome 4, suggesting shared mechanistic roles across tissue types. Overall, CLVS2 represents an emerging genetic modifier in neurodegenerative and systemic diseases involving endosomal-lysosomal dysfunction.