The c.146C>A variant in the glucokinase gene, GCK causes an amino acid change of threonine to asparagine at codon 49 (p.(Thr49Asn)) 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 has a REVEL score of 0.691, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on GCK function. This variant is absent from gnomAD v4.1.2 (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 30257192, Clinvar, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with seven informative meioses in 2 families (PP1_Strong; PMID: 30257192, internal lab contributors). Functional studies demonstrated the p.Thr49Asn protein had a relative activity index (RAI) < 0.5; however, the wild-type kinetic parameters didn’t pass the MDEP quality control, and PS3 could not be applied (PMID: 30257192). In summary, this variant meets the criteria to be classified as pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.1.0, approved 10/10/2025): PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting, PP2.