SEPSECS encodes O-phosphoseryl-tRNA:selenocysteine-tRNA synthase, an enzyme that catalyzes the terminal step of selenocysteine biosynthesis by converting O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) 1. This reaction is essential for the incorporation of selenocysteine, the 21st genetically encoded amino acid, into selenoproteins 1. The enzyme functions as a tetramer with four active sites but binds only two tRNA molecules due to structural constraints imposed by its C-terminal α-helical extension, which evolved specifically in vertebrates to optimize tRNA binding and prevent complex aggregation 23. Structurally, tRNA binding induces conformational changes that organize the active sites through electrostatic interactions between the tRNA's acceptor, TΨC, and variable arms with specific helices of SEPSECS 3. Disease-wise, SEPSECS mutations cause Pontocerebellar Hypoplasia Type 2D (PCH2D), a rare neurological disorder characterized by progressive cerebellar atrophy, microcephaly, intellectual disability, and motor dysfunction 45. The protein also serves as an autoantigen (SLA/LP) in autoimmune hepatitis, where anti-SEPSECS antibodies are associated with more severe disease phenotypes 16.