Many genetic alterations have been reported at this locus including HhAntag691 structure deletions, duplications, nonsense, and missense mutations. Genotype/phenotype correlations have been described, with some variation. In general, mutations that abolish enzyme function are associated with a relatively uniform clinical and biochemical presentation. Animal models of OTCD that have been characterized and are readily available include the spf mouse and the spf-ash mouse. These models are currently maintained on a mixed background, B6EiC3Sn, which may limit certain issues of experimental design. Herein, we describe a new spontaneous hypomorphic missense mutation in the C57BL/6J-Otcspf-J/J that produces a new model of mild OTCD. Spf-J mice display normal plasma ammonia and plasma orotic acid at baseline and milder amino acid perturbations when compared to their predecessors. Despite this mild plasma biochemical phenotype, cerebral amino acid concentrations were elevated at baseline and, unlike WT, were depleted during a systemic immune response suggesting altered cerebral amino acid metabolism or transport. Overall, this mouse model is not only useful for further characterization of functional domains of the OTC enzyme, but is also useful for investigating the pathophysiology of cerebral amino acid metabolism in UCD. Due to the inheritance of OTCD, the phenotypic expression of the disease severity in patients is dependent upon the nature of the mutation, genetic background and in females, Xinactivation in the liver. In males, this disorder classically manifests with symptomatic hyperammonemia in infancy, although milder alleles have been described. In addition, phenotypic variability can be seen in males within the same family with the same mutation suggesting modifier alleles may play a role. Late-onset symptoms of OTCD, due to milder enzyme defects, may manifest in men as late as the fifth or sixth decade given the right precipitant, such as the Atkins’ diet. Galloway et al. described a previously healthy male who experienced his first documented hyperammonemic episode at 13 years of age. The precipitant of this episode was unknown. On admission to hospital, his ammonia was 750 μmol/L and hemodialysis was initiated. Urine orotate was 813 μmol/mmol creatinine, suggesting a diagnosis of OTCD. A subsequent liver biopsy demonstrated OTC enzyme activity to be 11% of normal. Molecular investigation revealed a lysine substitution for asparagine in the OTC protein. This amino acid substitution in the OTC enzyme is identical to the mutation described here in the spf-J mouse. Similar to the reported patient, the K80N mutation results in a reduction in enzyme activity to *11–12% in spf-J. The mutation lies outside the substrate binding and catalytic regions of the enzyme and may be related to homo-oligomerization or stability of the enzyme. In our studies, we demonstrated normal levels of OTC mRNA and OTC protein that was below the limit of detection by immunoblot. These findings lead us to suggest that the K80N mutation may destabilize the enzyme, leading to its early degradation.