CFAP221 (Cilia and Flagella Associated Protein 221) is essential for motile cilium assembly and function, playing a critical role in ciliary central apparatus structure and sperm flagellar development 1. The protein localizes to ciliary and flagellar axonemes, particularly in elongating sperm cells during spermatogenesis 2. CFAP221 interacts with other flagellar development proteins including CFAP74, CFAP194, CFAP246, and CFAP297, suggesting coordinated regulation of ciliary/flagellar biogenesis 2. Pathogenic variants in CFAP221 cause primary ciliary dyskinesia (PCD), a rare genetic disorder characterized by impaired mucociliary clearance 3. Unlike typical PCD, CFAP221 deficiency presents as a mild form with normal ciliary ultrastructure and beat frequency, but manifests aberrant circular ciliary motion and reduced beat frequency 1. Additionally, biallelic CFAP221 variants cause asthenoteratozoospermia with severely malformed sperm flagella and impaired male fertility, though intracytoplasmic sperm injection can enable successful reproduction 2. CFAP221 deficiency is also associated with congenital hydrocephalus in mouse models, suggesting broader neurological complications 4. Clinical recognition of CFAP221-related disease requires genetic testing, as standard diagnostic algorithms may miss this atypical PCD presentation 5.