HMBS (hydroxymethylbilane synthase) catalyzes the sequential polymerization of four porphobilinogen molecules to form hydroxymethylbilane (preuroporphyrinogen), a critical step in heme biosynthesis 1. The enzyme functions through assembly of a dipyrromethane cofactor that serves as a primer for tetrapyrrole product assembly, with the cofactor remaining bound after product release 2. HMBS deficiency causes acute intermittent porphyria (AIP), an autosomal dominant disorder affecting heme biosynthesis 3. AIP is the most common acute hepatic porphyria with estimated symptomatic prevalence of 1 in 100,000, predominantly affecting women aged 15-50 years 4. Over 90% of AIP patients exhibit decreased erythrocyte HMBS activity (<70%), with missense mutations being most common (34.4%), followed by splice mutations (28.1%) 5. Clinically, HMBS mutations trigger acute attacks characterized by severe abdominal pain and neurological symptoms, with long-term complications including hypertension, chr11 kidney disease, and hepatocellular carcinoma 4. Approximately one-third of clinical variants are missense mutations designated as "variants of uncertain significance," though systematic functional characterization of amino acid substitutions now enables discrimination between pathogenic and benign variants 6. Management includes biochemical screening via urinary porphobilinogen and δ-aminolevulinic acid, genetic confirmation via HMBS sequencing, and acute attack treatment with intravenous hemin 4.