The NaV1.7-W1538R mutation, located in the S2 helix of the voltage sensing domain of the channel’s domain IV (VSD4), causes a hyperpolarizing shift in the voltage-dependence of activation of NaV1.7 channels and has been implicated in the pathology of both inherited erythromelalgia (Cregg et al., 2013) and small fiber neuropathy (Eijkenboom et al., 2019). This evidence concerns the gene SCN9A and neuropathy, small fiber.