SEPTIN12 is a testis-enriched, filament-forming cytoskeletal GTPase essential for male fertility. Functionally, SEPTIN12 serves as a critical structural component during spermiogenesis, interacting with α- and β-tubulins to coordinate sperm head morphogenesis and tail elongation 1. SEPTIN12 forms octameric filamentous complexes with SEPTIN7, SEPTIN6, and SEPTIN2 at the sperm annulus, a septin-based ring structure required for sperm tail structural integrity and motility 2. At the sperm head-tail junction, SEPTIN12 interacts with nuclear membrane protein SUN5 and LaminB1, anchoring the proximal centriole to the nucleus and maintaining the critical head-to-tail connection 3. SEPTIN12 expression is hormonally regulated via androgen and estrogen receptor binding sites in its promoter, responding to 17β-estradiol and 5α-dihydrotestosterone 4. Post-translationally, SEPTIN12 phosphorylation at Ser198 by Protein Kinase A negatively regulates its polymerization, with phosphomimetic mutations causing impaired sperm motility and annulus loss 2. CDC42 also negatively modulates SEPTIN12 polymerization during sperm head terminal differentiation 5. Clinically, SEPTIN12 mutations and polymorphisms associate with male infertility phenotypes including teratozoospermia, oligozoospermia, immotile sperm, and Sertoli cell-only syndrome 6, 7. Truncated SEPTIN12 variants inhibit filament formation and cause bent-tail sperm with nuclear DNA damage 6. SEPTIN12 is classified as having limited evidence for male infertility causation 8.