CLTCL1 encodes clathrin heavy chain-like 1 (CHC22), a clathrin isoform mediating specialized intracellular membrane trafficking distinct from the ubiquitous CHC17. CHC22 functions primarily in glucose homeostasis by mediating insulin-responsive GLUT4 glucose transporter trafficking from the ERGIC (endoplasmic-reticulum-to-Golgi intermediate compartment) directly to intracellular storage compartments 1. This specialized transport route requires CHC22 interaction with SNX5/SNX6 and the tether protein p115 through bipartite N- and C-terminal binding sites 1. Unlike CHC17's housekeeping endocytic functions, CHC22 enables mobilization of GLUT4 to the plasma membrane in response to insulin signaling 2. CLTCL1 exhibits population-specific genetic variation; the V1316 allele, enriched in farming populations, shows reduced GLUT4 trafficking efficiency compared to M1316, suggesting ancestral dietary selection influenced human metabolic adaptation 2. Disease associations include emerging evidence linking CLTCL1 to osteosarcoma prognosis and progression, where CLTCL1 knockdown significantly altered tumor cell proliferation, migration, and apoptosis 3. CLTCL1 mutations have been identified in schizophrenia pedigrees 4 and the gene is located within the 22q11.2 microdeletion region implicated in congenital heart disease and oculo-auriculo-vertebral spectrum 56. Additionally, CLTCL1 was identified as a painlessness gene with potential therapeutic implications for analgesic development 7.