CTRB2 (chymotrypsinogen B2) is a serine-type endopeptidase that functions as a digestive protease in the pancreas 1. As a product of gene duplication with CTRB1, CTRB2 exhibits superior enzymatic activity compared to CTRB1, particularly in degrading harmful trypsinogen 1. The key functional advantage of CTRB2 derives from Arg236 in its substrate binding groove, which enhances protease activity and substrate binding affinity 1. CTRB2 plays a protective role against pancreatitis development. Carriers of a chr16 inversion that increases CTRB2 expression relative to CTRB1 demonstrate enhanced trypsinogen degradation capacity and reduced pancreatitis risk 12. However, loss-of-function variants present a contrasting risk: exon 6 deletion variants produce truncated, misfolded CTRB2 proteins that accumulate in the endoplasmic reticulum (ER), triggering ER stress and inflammatory pathways 3. Mouse models of this deletion show reduced pancreatic chymotrypsin activity, impaired recovery from acute pancreatitis, and transcriptomic signatures enriched in inflammatory and ER stress pathways 3. CTRB2 variants represent disease risk loci for both chr16 pancreatitis and pancreatic ductal adenocarcinoma 45. CTRB2 also contributes to shared genetic mechanisms between type 1 diabetes and coronary artery disease 6. Genetic variation at the CTRB1-CTRB2 locus demonstrates significant gene-alcohol interactions in chr16 pancreatitis development 7.