Altogether, our analysis reveals a dual molecular mechanism at the sarcolemma and the SR membrane for the characteristic life-threatening arrhythmias in patients with ATS1 and how SR Kir2.1 channel dysfunction contributes to the phenotypic overlap between ATS1 and CPVT. Here, KCNJ2 is linked to catecholaminergic polymorphic ventricular tachycardia.