ENAM encodes enamelin, a structural protein essential for dental enamel formation and mineralization. During amelogenesis, ENAM functions in enamel matrix organization and extension during the secretory stage of enamel development 1. The protein localizes to the extracellular matrix and endoplasmic reticulum lumen, where it contributes to the structural integrity of forming tooth enamel through protein-protein interactions. Mutations in ENAM cause amelogenesis imperfecta (AI), a heritable developmental disorder affecting enamel structure in all or nearly all teeth 2. ENAM mutations are implicated in autosomal dominant forms of AI 2, resulting in hypoplastic, hypomineralized, or combined enamel phenotypes that may cause tooth sensitivity, discoloration, and increased susceptibility to wear 1. Beyond pathogenic mutations, natural genetic variation in ENAM influences normal enamel phenotypes; the derived allele of SNP rs7671281 (C14625T) is associated with significantly thinner enamel in an additive genetic model 3. ENAM polymorphisms also contribute to dental caries susceptibility. The rs3796704 SNP shows significant association with increased caries risk, particularly in Caucasian populations 4. ENAM is recognized among key enamel-formation genes (alongside AMELX, AMBN, MMP20, KLK4) with substantial impact on caries genetics 5. Clinically, AI management involves early preventive and restorative interventions throughout childhood and into adulthood 2.