CFAP65 (cilia and flagella associated protein 65) is essential for sperm flagellar structure and motility. Primary function: CFAP65 anchors at the base of the C2a projection within the axoneme's central pair apparatus, where it interacts with proteins like CFAP70 and MYCBPAP to maintain axonemal integrity 1. During spermiogenesis, CFAP65 is required for acrosome biogenesis, manchette organization, and mitochondrial sheath assembly, forming a cytoplasmic protein network with MNS1, RSPH1, TPPP2, ZPBP1, and SPACA1 2. Mechanism: Loss of CFAP65 causes disorganization of the sperm head-shaping microtubule structure and impairs protamine precursor removal, leading to nuclear condensation defects and C2a projection disintegration 1. Disease relevance: CFAP65 mutations cause multiple morphological abnormalities of sperm flagella (MMAF) and asthenoteratozoospermia, accounting for significant male infertility cases 34. Clinical significance: CFAP65-deficient males present with severe sperm flagellar defects and infertility, with high hydrocephalus incidence but organ-specific ciliary involvement—respiratory cilia remain largely unaffected 1. Intracytoplasmic sperm injection (ICSI) offers good reproductive prognosis for affected individuals 5. CFAP65 also shows potential as a prognostic marker in colon cancer, with low expression correlating with reduced disease-free survival 6.