CLTC encodes clathrin heavy chain, the primary structural protein of clathrin-coated pits and vesicles that mediates clathrin-dependent endocytosis 1. Beyond its canonical role in membrane trafficking, CLTC functions as a component of the TACC3/ch-TOG/clathrin complex, which stabilizes kinetochore fibers during mitosis and maintains kinetochore fiber tension 1. CLTC also participates in early autophagosome formation and interacts with DNAJC6 to recruit uncoating machinery 1. Additionally, CLTC regulates lipid metabolism through R-loop formation and inhibits NLRP3 inflammasome activity in hepatocytes 23. Pathogenic CLTC variants cause intellectual developmental disorder 56 (IDD56), an autosomal dominant condition characterized by intellectual disability ranging from mild to moderate/severe 14. De novo missense, in-frame, nonsense, and frameshift variants have been identified in affected individuals 51. Missense and in-frame variants are associated with additional features including microcephaly, corpus callosum hypoplasia, and epilepsy, potentially through dominant-negative mechanisms, while nonsense and frameshift variants may cause haploinsufficiency 1. CLTC variants also constitute fusion partners in histiocytic neoplasms, including ALK-positive histiocytosis and juvenile xanthogranuloma, where CLTC-ALK and CLTC::SYK fusions drive kinase-dependent pathogenesis 67.