The c.388C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to glutamic acid at codon 130 (p.(Gln130Glu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Functional studies demonstrated the p.Gln130Gly protein has transactivation and DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32017842). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 32017842, internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.388C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting.