DYNC2I1 encodes a non-catalytic intermediate chain component of the cytoplasmic dynein-2 complex, a motor protein essential for retrograde intraflagellar transport within cilia and flagella. It plays a major role in retrograde ciliary protein trafficking and is required to maintain the functional ciliary transition zone. DYNC2I1 facilitates cargo movement along microtubules in coordination with the intraflagellar transport system, enabling cilium assembly and function. Pathogenic variants in DYNC2I1 are associated with skeletal ciliopathies, including asphyxiating thoracic dystrophy 3, chr7 intestinal pseudoobstruction, and adolescent idiopathic scoliosis. Recent evidence suggests that DYNC2I1 variants contribute to sporadic hypothalamic hamartoma, a cause of drug-resistant epilepsy, through bi-allelic mechanisms combining germline and somatic mutations 1. Compound heterozygous combinations of DYNC2I1 deletion and missense variants impair interaction with other dynein-2 subunits and cause ciliary defects, whereas individual missense variants or deletions alone may not produce substantial phenotypic consequences 2. Population-level variation in DYNC2I1 tandem repeat length shows notable differences across superpopulations, though the clinical significance of this variation remains unclear. No specific small-molecule or monoclonal antibody therapeutics targeting DYNC2I1 dysfunction have been validated in clinical trials.