HNF1A encodes a transcription factor critical for pancreatic and hepatic development and function. As a DNA-binding transcription factor, HNF1A regulates glucose homeostasis and renal glucose absorption through tissue-specific gene regulation 1. The protein functions as a transcription activator, controlling expression of metabolic genes including A1CF, which orchestrates an RNA splicing program essential for β cell function 2. Mechanistically, HNF1A acts as a transcription factor that binds DNA cis-regulatory regions and cooperates with other nuclear factors to regulate target gene expression in pancreatic β cells and hepatocytes 1. A critical HNF1A-A1CF transcription-splicing axis coordinates β cell-specific programs disrupted in type 2 diabetes 2. HNF1A mutations cause Maturity-Onset Diabetes of the Young type 3 (MODY3), the most common monogenic diabetes form, with disease penetrance varying substantially by clinical context (32% in population-based cohorts to 98% in probands) 3. HNF1A-MODY patients exhibit differential sulfonylurea sensitivity and respond therapeutically to these agents 4. HNF1A mutations also associate with type 1 diabetes, familial hepatic adenomas, and potentially premature ovarian failure 5. Correct HNF1A diagnosis is clinically critical, as it determines treatment strategy—sulfonylureas rather than insulin 6. Polygenic HNF1A variants modulate type 2 diabetes risk, with loss-of-function variants predisposing and gain-of-function variants protective 2.