Recent evidence highlight that the desmosomal proteins, PKP2 and DSP, contain putative calpain binding sites that when exposed through a subset of ARVC-related mutations, may trigger their vulnerability to calpain-mediated degradation (Kirchner et al. 2012; Ng et al. 2019; Hoover et al. 2021). The gene discussed is PKP2; the disease is arrhythmogenic right ventricular cardiomyopathy.