The c.480T>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to glutamine at codon 160 (p.(Asp160Glu)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.893, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia) (PP4_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Two other missense variants at the same residue, c.478G>A (p.Asp160Asn) and c.478G>C (p.Asp160His), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). The nucleotide change c.480T>G, which causes the same amino acid change, has been classified as likely pathogenic for monogenic diabetes by the ClinGen MDEP; however, PS1_Moderate was not applied to avoid circularity. In summary, c.480T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PP4_moderate, PM5_strong, PP2, PP3, PM2_supporting.