The c.1129C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 377 (p.(Arg377Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 contributors). This variant segregated with diabetes, with 4 informative meioses in a family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributors). Another missense variant, c.1129C>T p.Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377Ser) (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Moderate, PM5_Supporting.