NT5C2 encodes a cytosolic 5'-nucleotidase that catalyzes dephosphorylation of purine nucleoside monophosphates, particularly IMP and GMP, and possesses phosphotransferase activity to transfer phosphates between nucleosides 12. Through these dual enzymatic activities, NT5C2 regulates intracellular purine nucleotide pools 12. In neural tissue, NT5C2 is enriched during neurodevelopment and regulates AMPK signaling and protein translation in neural progenitor cells, with reduced expression linked to psychiatric risk 3. Clinically, NT5C2 mutations are the primary drivers of thiopurine chemotherapy resistance in relapsed acute lymphoblastic leukemia (ALL), occurring in 17-65% of cases depending on relapse timing 4. Gain-of-function NT5C2 mutations increase nucleosidase activity, reducing active metabolite accumulation of 6-mercaptopurine 5. Alternatively spliced NT5C2 isoforms incorporating exon 6a similarly confer 6-mercaptopurine resistance comparable to hotspot mutations 6. Beyond ALL, NT5C2 genetic variants associate with coronary heart disease risk and intracranial aneurysm susceptibility 78, while elevated NT5C2 expression driven by fatty acid oxidation-induced HIF-1α activation contributes to hyperuricemia and gout pathogenesis 9. Autosomal recessive NT5C2 mutations cause spastic paraplegia 45.