The c.48C>G variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 16 (p.(Tyr16*)) of NM_175914.5. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes/neonatal hyperinsulinism, with 13 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes or diazoxide-responsive hyperinsulinemic hypoglycemia; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 20164212, 16917892, 17407387, 18268044, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). In summary, c.48C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP1_Strong, PP4_Moderate, PM2_Supporting.