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CEL-MODY, diabetes with pancreatic lipomatosis and exocrine dysfunction, is due to dominant frame-shift mutations in the acinar cell carboxyl-ester lipase gene (CEL). As Cel knock-out mice do not express the phenotype and the mutant protein has an altered, intrinsically disordered tandem repeat domain, we hypothesized that the disease mechanism might involve a negative effect of the mutant protein. In silico analysis showed that the pI of the tandem repeat was markedly increased from pH 3.3 in wild-type (WT) to 11.8 in mutant (MUT) human CEL. By stably over-expressing CEL-WT and CEL-MUT in HEK293 cells, we found similar glycosylation, ubiquitination, constitutive secretion and quality control of the two proteins. The CEL-MUT protein demonstrated, however, a high propensity to form aggregates found intracellularly and extracellularly. Different physico-chemical properties of the intrinsically disordered tandem repeat domains of WT and MUT proteins may contribute to different short-range and long-range interactions with the globular core domain and other macromolecules, including cell membranes. Thus, we propose that CEL-MODY is a protein misfolding disease caused by a negative gain-of-function effect of the mutant proteins in pancreatic tissues.