The c.926G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 309 (p.(Arg309His)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.765, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the South Asian subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hyperinsulinemic hypoglycemia and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). This variant segregated with diabetes and/or diazoxide-responsive hyperinsulinemic hypoglycemia, with 4 informative meioses in 1 family (PP1_Moderate; internal lab contributors). Another missense variant, c.925C>T p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309His (PM5_Supporting). In summary, c.926G>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 2.0.0, approved 10/11/2023): PP1_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting, PM5_Supporting.