Paroxysmal extreme pain disorder: genes and variants

Genes linked to Paroxysmal extreme pain disorder

• SCN9A: Sodium channel protein type 9 subunit alpha

  The protein forms Nav1.7, a voltage-gated sodium channel that amplifies electrical signals in peripheral sensory neurons. Changes in Nav1.7 activity can produce either excessive pain or congenital insensitivity to pain, making SCN9A central to pain biology.

  4 disease-causing and 35 uncertain variants in SCN9A are linked to Paroxysmal extreme pain disorder.

• IDH1: Isocitrate dehydrogenase [NADP] cytoplasmic

  It normally generates alpha-ketoglutarate and NADPH in the cytosol and peroxisomes. Recurrent cancer-associated variants at R132 acquire the ability to produce D-2-hydroxyglutarate, an oncometabolite that rewires epigenetic regulation in glioma, leukemia, and other tumors.

  1 disease-causing and 0 uncertain variants in IDH1 are linked to Paroxysmal extreme pain disorder.

Known disease-causing variants in Paroxysmal extreme pain disorder

Same protein, different disease

• Generalized epilepsy with febrile seizures plus is also caused by SCN9A variants; they fall mostly in different places as the Paroxysmal extreme pain disorder variants (14 disease-causing).
• Neuropathy, hereditary sensory and autonomic, type 2A is also caused by SCN9A variants; they fall mostly in different places as the Paroxysmal extreme pain disorder variants (14 disease-causing).
• Primary erythromelalgia is also caused by SCN9A variants; they fall mostly in different places as the Paroxysmal extreme pain disorder variants (6 disease-causing).
• Channelopathy-associated congenital insensitivity to pain is also caused by SCN9A variants; they fall mostly in different places as the Paroxysmal extreme pain disorder variants (3 disease-causing).

Diseases related to Paroxysmal extreme pain disorder

• Amyotrophic lateral sclerosis, also linked to SCN9A
• Generalized epilepsy with febrile seizures plus, also linked to SCN9A
• Cardiac arrhythmia, also linked to SCN9A
• Acute myeloid leukemia, also linked to IDH1
• Epilepsy, also linked to SCN9A
• Neuropathy, hereditary sensory and autonomic, type 2A, also linked to SCN9A
• Enchondromatosis, also linked to IDH1
• Primary erythromelalgia, also linked to SCN9A
• Maffucci syndrome, also linked to IDH1
• Focal epilepsy, also linked to SCN9A
• Channelopathy-associated congenital insensitivity to pain, also linked to SCN9A
• Lennox-Gastaut syndrome, also linked to SCN9A

Frequently asked questions

Which genes are linked to Paroxysmal extreme pain disorder?

In CATVariant, Paroxysmal extreme pain disorder is linked to 2 analyzed proteins: SCN9A (Sodium channel protein type 9 subunit alpha) and IDH1 (Isocitrate dehydrogenase [NADP] cytoplasmic).

How many genetic variants are linked to Paroxysmal extreme pain disorder?

46 variants: 5 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 35 are of uncertain significance or have conflicting reports.

Which uncertain variants in Paroxysmal extreme pain disorder look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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