The c.1265G>T variant in the glucokinase, GCK, causes an amino acid change of arginine to leucine at codon 422 (p.Arg422Leu) 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 an incomputable gnomAD v4.1.2 Grpmax filtering allele frequency due to no more than one copy in any non-founder subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 23771925, 33218273, internal lab contributors). At least one of these individuals had a phenotype highly consistent for GCK-related hyperglycemia (persistent elevated fasting glucose 5.5-8 mmol/L (3x) and HbA1c 5.6 - 7.6% (4x)) (PP4_Moderate; PMID: 33218273). Another missense variant at the same residue, c.1265G>C (p.Arg422Pro), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant has a REVEL score of 0.635, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. In summary, c.1265G>T 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, approved 10/10/2025): PS4_Moderate, PP4_Moderate, PM2_Supporting, PM5_Supporting, PP2.