Sucrase-isomaltase (SI) is a brush border enzyme that catalyzes the final stage of carbohydrate digestion in the small intestine. The enzyme cleaves disaccharides and oligosaccharides through its dual enzymatic activities: sucrase hydrolyzes sucrose, while isomaltase processes both α-1,4- and α-1,6-linked oligosaccharides. SI is synthesized in jejunal enterocytes, trafficked through the Golgi apparatus, and localized predominantly to the microvillus membrane where it performs its catalytic function 1. In congenital sucrase-isomaltase deficiency, a transport defect traps the enzyme precursor in trans-Golgi compartments, preventing its delivery to the apical membrane and resulting in loss of enzymatic activity and carbohydrate malabsorption 2. At the population level, gnomAD v4.1 classifies SI as LoF-tolerant (LOEUF=1.01), yet ClinVar documents 162 pathogenic variants, demonstrating that population-level constraint and clinical disease pathogenicity represent distinct signals. Therapeutically, saccharide analogs like voglibose and celgosivir target SI to modulate glucose absorption and viral replication, respectively, establishing this enzyme as a clinical intervention point in metabolic and infectious disease contexts.