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Arrhythmias account for approximately 250,000 deaths in the U.S annually, with nearly half being associated with heart disease. Arrhythmogenic disorders are broken down into a variety of subcategories, with the vast majority being primarily caused by either activity changes or variants in ion channels/exchangers. Arrhythmogenic cardiomyopathy (ACM) is a unique form of heart disease that is primarily hereditary, where variants in genes encoding structural proteins are the most frequent cause of disease formation. Variants within desmosomal genes are one of the leading predisposing factors to ACM, primarily characterized by fibro-fatty infiltration in the ventricular myocardium with an increased propensity for ventricular arrhythmias. This frequently results in sudden cardiac death, even prior to the detection of any cardiac structural abnormalities. Previous work on a familial ACM variant in desmoplakin (DSP) (p.R451G) identified a post-translational degradation of DSP that stemmed from increased sensitivity to the protease calpain, a pattern identified in additional pathogenic variants. Despite these findings, incomplete penetrance within most familial ACM cases complicates understanding of the associated molecular pathways, as well as determining the external factors that contribute to disease development. While the generation of murine models have significantly contributed to the understanding of disease progression, most utilized knock-out or transgenic techniques, limiting the potential translational impact. Our group has developed one of the first mouse models of ACM derived from a human variant by introducing the murine equivalent of the R451G variant into endogenous desmoplakin (DspR451G/+). Mice homozygous for this variant displayed embryonic lethality. While DspR451G/+ mice were viable with reduced expression of DSP, no presentable arrhythmogenic phenotype was identified at baseline. Following acute stress through catecholaminergic challenge, DspR451G/+ mice displayed more frequent and prolonged arrhythmias compared to their control littermates. Chronic stress using pressure overload resulted in reduced cardiac performance, increased chamber dilation, and more rapid progression to heart failure in the DspR451G/+ mice. Finally, localization patterns in a key protein associated with DSP, connexin-43, were identified in the DspR451G/+ cardiac tissue. In summary, this model displays a phenotype only following cardiac stress, suggesting this model may be a useful tool for understanding the influences of environmental factors on disease penetrance. Further evaluation of variants of unknown pathogenicity within an N-terminal mutation hotspot of DSP determined calpain sensitivity may be a shared mechanism in DSP variants, which can be a predictor model for those of unknown pathogenicity. These studies highlight the need for personalized medicine based on the phenotypic variability among patients with different variants, and even among those in the same family.