The c.629T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 210 (p.(Met210Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.982, which is greater than the MDEP threshold of 0.70 (PP3). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Met210Thr has Kcat/S0.5<0.5 (PS3_Supporting; PMID: 14517946, DOI:10.1007/s001250051289). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency of due to 0 copies observed in the European non-Finnish population and only 1 copy in another subpopulation (Latino/admixed), thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in 11 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 25555642, 9049484, ClinVar ID: 804852, internal lab contributor). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributor). This variant segregated with diabetes, with 5 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). Taken together, the evidence supports the classification of c.629T>C as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PS4, PS3_Moderate, PP2, PP3, PM2_Supporting.