SPACA6 (sperm acrosome associated 6) is an essential sperm surface protein required for mammalian fertilization, specifically functioning in sperm-egg membrane fusion rather than initial adhesion 1. The protein localizes to the sperm equatorial segment following acrosomal reaction and remains present during fertilization 1. Structurally, SPACA6 contains a two-domain ectodomain with a four-helix bundle and immunoglobulin-like β-sandwich connected by a flexible linker, making it a founding member of the IST superfamily of fertilization-associated proteins alongside IZUMO1 2. SPACA6 functions as part of a conserved trimeric sperm complex with IZUMO1 and TMEM81 that mediates sperm-egg interaction 3. During fertilization, SPACA6 participates in a phagocytosis-like process termed SEAL (sperm engulfment activated by IZUMO1-JUNO linkage), where it helps facilitate the oocyte's engulfment of sperm to initiate membrane fusion 4. Male mice lacking SPACA6 are infertile, with sperm unable to fuse with oocytes despite accumulating in the perivitelline space 1. Anti-SPACA6 antibodies can inhibit human fertilization, indicating its clinical relevance for male fertility 1.