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Background: Genetic variants in voltage-gated sodium channels (Na_v) encoded by <i>SCNXA</i> genes, responsible for I_Na, and K_v4.3 channels encoded by <i>KCND3</i>, responsible for the transient outward current (I_to), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that K_v4.3 and Na_v variants regulate each other’s function, thus modulating I_Na/I_to balance in cardiomyocytes and I_Na/I_(A) balance in neurons. Methods: Bicistronic and other constructs were used to express WT or variant Na_v1.5 and K_v4.3 channels in HEK293 cells. I_Na and I_to were recorded. Results: <i>SCN5A</i> variants associated with BrS reduced I_Na, but increased I_to. Moreover, BrS and SCA19/22 <i>KCND3</i> variants associated with a gain of function of I_to, significantly reduced I_Na, whereas the SCA19/22 <i>KCND3</i> variants associated with a loss of function (LOF) of I_to significantly increased I_Na. Auxiliary subunits Na_vβ1, MiRP3 and KChIP2 also modulated I_Na/I_to balance. Co-immunoprecipitation and Duolink studies suggested that the two channels interact within the intracellular compartments and biotinylation showed that LOF <i>SCN5A</i> variants can increase K_v4.3 cell-surface expression. Conclusion: Na_v and K_v4.3 channels modulate each other’s function via trafficking and gating mechanisms, which have important implications for improved understanding of these allelic cardiac and neuronal syndromes.