In this study, we generate a PKP2 genetic knock-in mouse model to demonstrate the sufficiency of a prevalent PKP2 RNA splicing mutation (human PKP2 IVS10-1G>C) to phenocopy key human ARVC features in mouse, including sudden death, ventricular arrhythmias (which include ventricular depolarization abnormalities serving as a primer for life-threatening arrhythmias, as well as electrophysiological alterations in sodium channel function and Nav1.5 protein localization), biventricular dysfunction, inflammation, desmosomal ultrastructural deficits and fibrofatty replacement of myocardium. Here, PKP2 is linked to arrhythmogenic right ventricular cardiomyopathy.