The c.1306A>T variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to phenylalanine at codon 436 (p.(Ile436Phe)) 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 0.8259, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). Three of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 2 informative meioses in 2 families (PP1; internal lab contributor). Additionally, another missense variant, c.1307T>A (p.Ile436Asn), has been classified as likely pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ile436Phe (PM5_Supporting). Taken together, this evidence supports the classification of c.1306A>T as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS4_Moderate, PP1, PP2, PP3, PM2_Supporting, PM5_Supporting.