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Pathogenic variants in the sodium channel gene SCN11A encoding for NaV1.9 have been associated with various pain loss and neuropathic pain conditions. We herein describe the novel heterozygous SCN11A variant c.197A&amp;gt;C; p.(Tyr66Ser) that is absent in controls and cosegregates with small fiber neuropathy in a mother-and-son duo. To a variable degree, but progressively over time, both patients developed positive and negative sensory symptoms and milder autonomic signs. Upon quantitative sensory testing, we found significant thermal hypoesthesia and pinprick hyperalgesia in both individuals. Rectangle, half-sine-, and sine-wave stimulation applied to hands and feet in both individuals revealed signs of axonal on\/off-like hyperexcitability, possibly due to continuous activation of CMi-fibers that are insensitive to mechanical stimulation (also known as sleeping nociceptors). Nerve conduction studies were unremarkable, whereas pain-related evoked potentials showed pathological responses in both individuals. The intraepidermal nerve fiber density was reduced at the index patient\u2019s distal leg. Patch-clamp analyses revealed that p.(Tyr66Ser) shifted both the voltage dependence of activation and steady-state inactivation of NaV1.9 to more depolarized potentials, accompanied by accelerated deactivation and a slowdown of the channel\u2019s inactivation kinetics. In addition, overexpression of the variant in mouse sensory neurons shortened the duration of individual action potentials and enhanced action potentials after hyperpolarization. In this translational n-of-two study, we present longitudinal data on disease progression and provide functional evidence that the SCN11A variant p.(Tyr66Ser) is a strong candidate to contribute to the patients\u2019 phenotype.<\/jats:p>","DOI":"10.1085\/jgp.202413691","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T06:20:27Z","timestamp":1757658027000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Altered NaV1.9 channel activity in two Tyr66Ser variant carriers with small fiber dysfunction"],"prefix":"10.1085","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8907-9899","authenticated-orcid":true,"given":"Noortje W.M.","family":"van den Braak","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gm5zw39","id-type":"ROR","asserted-by":"publisher"}],"name":"Scientific Center for Neuropathic Pain Aachen (SCNAACHEN), Uniklinik RWTH Aachen 1 , 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