In silico analyses alongside cell and bacterial expression studies of desmosomal mutant proteins provided key insights into demonstrating the vulnerability of a subset of ARVC mutations in PKP2 (C-terminus: C796R, S615F, C693fsX741, and K654Q) and DSP (N terminus: R415G, S299R, S442F, and S507F) to rapid protein degradation (and loss of cell-cell junction localization) due to increased surface exposure to calpain (Kirchner et al. 2012; Ng et al. 2019). Here, PKP2 is linked to Arrhythmogenic right ventricular dysplasia.