EEFSEC encodes a specialized eukaryotic elongation factor required for incorporating selenocysteine, the 21st proteinogenic amino acid, at UGA codons during translation 12. The protein functions through a multi-step mechanism where SECISBP2 binds SECIS sequences and contacts ribosomal protein RPS27A/eS31, followed by GTP-bound EEFSEC delivering selenocysteinyl-tRNA(Sec) to the 80S ribosome in a preaccommodated state 2. After GTP hydrolysis, EEFSEC dissociates, allowing selenocysteinyl-tRNA(Sec) accommodation and peptide synthesis 2. Structurally, EEFSEC adopts a chalice-like conformation with four domains and exhibits similar binding affinities for GDP, GTP, and other guanine nucleotides 1. Unlike canonical elongation factors, nucleotide exchange induces conformational changes in domain 4 rather than domain 1 1. Biallelic EEFSEC variants cause a selenopathy characterized by progressive neurodegeneration, global developmental delay, spasticity, ataxia, seizures, and cerebellar atrophy 34. This disorder results from reduced selenoprotein levels due to impaired EEFSEC function 3. EEFSEC variants have also been associated with preterm birth 5 and periodontitis Grade C 6, highlighting its broader clinical significance beyond selenoprotein biosynthesis.