Objective: Hypokalemic periodic paralysis (HypoPP) is characterized by reversible attacks of flaccid muscle weakness caused by a sustained sarcolemmal membrane depolarization. Attacks are accompanied by decreased blood potassium triggered by rest after strenuous exercise, by a meal rich in carbohydrates, or by exposure to cold. HypoPP is caused by voltage sensor (S4) mutations in either the a- subunit of the Na_V1.4 channel or the homologous a₁-subunit of the skeletal muscle calcium channel, Ca_V1.1. Recent studies have shown that HypoPP mutations generate an aberrant conductance (w- pore) in the channel that destabilizes the membrane potential. We characterized the gating and putative -currents of R222G, a novel HypoPP mutation in DI-S4, to test the hypothesis that gating pore currents are a major disease-causing mechanism in HypoPP. Methods: Whole-cell patch-clamp recordings on transiently transfected HEK293 cells were performed to characterize the gating of WT and R222G sodium channels. Leak currents of WT-, R222G-injected and uninjected Xenopus oocytes were recorded with the cut-open technique under various recording conditions. Results: R222G shifted activation about 10 mV and steady-state fast inactivation about 5 mV into hyperpolarized direction. R222G enhanced slow inactivation by shifting the steady- state curve into hyperpolarized direction. R222G permits a transmembrane conductance for small cations at hyperpolarized potentials but not for larger cations. Conclusion: Our results are consistent with the idea that charge neutralizing mutations in voltage sensors may generate w-currents. The altered gating of R222G does not explain the phenotype. The fact that this mutation is in a different location than previous HypoPP mutations expands the understanding of w-currents as a contributor to the HypoPP pathogenesis.