The TMEM43 ‐ P386S mutation causes arrhythmogenic right ventricular cardiomyopathy (ARVC) by mislocalizing itself from nuclear envelope (NE) to cytoplasm, disrupting lamin B2 (a novel TMEM43 interactor) localization, NE integrity and chromatin accessibility, causing hyper ‐ phosphorylation and reduced expression/clustering of ryanodine receptor type 2 (RYR2), enhanced sarcoplasmic reticulum (SR) calcium leak and arrhythmias, which can be rescued by flecainide or KN93. Here, TMEM43 is linked to arrhythmogenic right ventricular cardiomyopathy.