CFAP69 encodes a cilia and flagella-associated protein that is essential for male fertility through its role in sperm flagellum assembly and stability 1. The protein localizes to the midpiece of sperm flagella and is highly expressed in testis 1. Mechanistically, CFAP69 is required during spermiogenesis for proper flagellum structure formation, as demonstrated by severe ultrastructural disruption in knockout mice despite preserved overall spermatogenesis 1. Homozygous loss-of-function mutations in CFAP69 cause autosomal-recessive multiple morphological abnormalities of the flagella (MMAF), characterized by immotile spermatozoa with short, coiled, absent, or irregular-caliber flagella 12. This condition results in severe asthenoteratozoospermia and male infertility, classified as spermatogenic failure 24 3. Clinical studies have identified novel pathogenic variants including frameshift mutations that reduce CFAP69 expression and disrupt sperm ultrastructure 3. Despite the severe sperm defects, assisted reproductive technology with intracytoplasmic sperm injection (ICSI) can achieve successful pregnancies in affected couples, offering therapeutic hope 3. CFAP69 interacts with other proteins involved in sperm assembly and flagella formation, including confirmed binding to SPEF2 4.