GSPT2 (G1 to S phase transition 2) is a GTPase component of the eRF1-eRF3-GTP ternary complex that mediates translation termination at stop codons (UAA, UAG, UGA) 1. The eRF1-eRF3-GTP complex binds stop codons in the ribosomal A-site, and GTP hydrolysis by GSPT2 induces conformational changes enabling ETF1/ERF1 accommodation 2. GSPT2 also functions in the SURF complex recruiting UPF1 to stalled ribosomes during nonsense-mediated decay of mRNAs with premature stop codons 3. Unlike its paralog GSPT1, GSPT2 functionally substitutes for yeast eRF3 4. Clinically, GSPT2 dysregulation associates with multiple disease contexts. Hemizygous GSPT2 variants cause X-linked neurodevelopmental disorder featuring intellectual disability, language impairment, autism, and epilepsy through dysregulation of cell-cycle progression and calcium/GABAergic signaling 5. GSPT2 deletions (Xp11.22) also cause syndromic intellectual disability with developmental delay and hypotonia 6. In cancer, GSPT2 overexpression correlates with poor prognosis in endometrial cancer, associated with aggressive pathological features and reduced overall survival 7. GSPT2 degraders show therapeutic potential in acute lymphoblastic leukemia, with the cereblon modulator SJ6986 demonstrating orally bioavailable, selective GSPT1/2 degradation and potent antileukemic activity 8.