Nociceptive sensory neurons transmit painful stimuli from the periphery to the central nervous system. Voltage-gated sodium (NaV) channels are instrumental for the generation of the corresponding electrical signals, but - so far - the sensory neuron-specific NaV1.9 only appeared to play a minor role. Recently, we identified a de novo heterozygous mutation in the SCN11A gene encoding for NaV1.9 and demonstrated the implication of NaV1.9 in human pain perception (Leipold et al., Nature Genetics, DOI 10.1038/ng.2767). Surprisingly, in affected individuals the mutation (L811P) leads to an inability to experience pain by conferring gain-of-function (GOF) properties to NaV1.9. Mutant channels activate at hyperpolarized voltages and display a slow-down of channel inactivation and deactivation, thereby causing sustained depolarization of nociceptor cells and alterations of action potential characteristics. This new channelopathy is different from other pain-related NaV channel disorders: a GOF of homologous NaV1.7 channels is associated with chronic pain, and loss of functional NaV1.7 channels causes congenital indifference to pain. To gain further insight into the mechanisms underlying the mutation we introduced the homologous L-to-P mutation into channel isoforms NaV1.4 (L802P), NaV1.7 (L957P) and NaV1.8 (L890P) and compared the functional parameters of wild-type and mutant channels by means of the whole-cell patch-clamp technique. The L-to-P mutation shifted the activation in all channel subtypes to hyperpolarized potentials in the order NaV1.9 > NaV1.7 > NaV1.4 > NaV1.8. Fast channel inactivation was slowed down most prominently in NaV1.9 and NaV1.8, followed by NaV1.7 and NaV1.4. These results show that a homologous L-to-P mutation affects channel activation and inactivation in a subtype-specific manner.