Given that the genetics of Brugada syndrome patients with high-risk atrioventricular block remains elusive, our genetic mapping and in vivo Cas9- and base-editing-mediated knockout models identifying rrad variants to induce a specific conduction phenotype with high-penetrance atrioventricular block, add insights on RRAD’s functional significance in humans and could have immediate value for antiarrhythmic therapy and device selection. The gene discussed is RRAD; the disease is Brugada syndrome.