CDKAL1 encodes a methylthiotransferase that catalyzes methylthiolation of N6-threonylcarbamoyladenosine (t(6)A) to form 2-methylthio-N6-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 in tRNAs reading adenine-starting codons, a modification critical for maintaining translational fidelity. The enzyme contains iron-sulfur clusters and localizes to the endoplasmic reticulum. CDKAL1 polymorphisms are strongly associated with type 2 diabetes (T2DM) susceptibility across multiple ethnic populations. The rs7756992 A/G, rs7754840, and rs10946398 variants all show significant associations with T2DM risk 12. Genetic variants also confer risk for gestational diabetes mellitus (GDM), particularly rs7754840 and rs7756992 34. The CDKAL1 rs10946398 polymorphism associates with post-transplant diabetes mellitus development 5 and non-alcoholic fatty liver disease (NAFLD) via the triglyceride-glucose index 6. Multiphenotype GWAS identified CDKAL1 among seven shared loci between type 2 diabetes and depression, suggesting pleiotropic mechanisms involving pancreatic islet and adipose tissue function 7. Notably, a CDKAL1 missense variant (P409L) decreased breast cancer cell sensitivity to docetaxel chemotherapy 8, indicating potential clinical relevance beyond metabolic disease. These findings establish CDKAL1 as a major genetic risk factor for metabolic disorders.