Neuropathy, hereditary sensory and autonomic, type 2A: genes and variants

Genes linked to Neuropathy, hereditary sensory and autonomic, type 2A

• 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.

  14 disease-causing and 1,213 uncertain variants in SCN9A are linked to Neuropathy, hereditary sensory and autonomic, type 2A.

• KIF1A: Kinesin-like protein KIF1A

  It transports synaptic vesicle precursors and other cargo along axonal microtubules toward nerve terminals. Pathogenic variants cause a broad KIF1A-associated neurological disorder spectrum including hereditary sensory neuropathy, spastic paraplegia, optic atrophy, ataxia, and developmental impairment.

  1 disease-causing and 1 uncertain variants in KIF1A are linked to Neuropathy, hereditary sensory and autonomic, type 2A.

Where Neuropathy, hereditary sensory and autonomic, type 2A variants cluster

• SCN9A Cytoplasmic (positions 1458–1514): 3 of 14 disease-causing changes, 7.5× more than its size predicts.
• SCN9A II (positions 726–989): 5 of 14 disease-causing changes, 2.7× more than its size predicts.
• SCN9A III (positions 1180–1488): 5 of 14 disease-causing changes, 2.3× more than its size predicts.

Known disease-causing variants in Neuropathy, hereditary sensory and autonomic, type 2A

Which prediction tools work for Neuropathy, hereditary sensory and autonomic, type 2A

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 83 out of 100
• AlphaMissense: 80 out of 100

Same protein, different disease

• Primary erythromelalgia is also caused by SCN9A variants; they fall mostly in different places as the Neuropathy, hereditary sensory and autonomic, type 2A variants (6 disease-causing).
• Paroxysmal extreme pain disorder is also caused by SCN9A variants; they fall partly in the same places as the Neuropathy, hereditary sensory and autonomic, type 2A variants (4 disease-causing).
• Hereditary spastic paraplegia is also caused by KIF1A variants; they fall mostly in different places as the Neuropathy, hereditary sensory and autonomic, type 2A variants (41 disease-causing).
• Neuropathy, hereditary sensory, type 2C is also caused by KIF1A variants; they fall mostly in different places as the Neuropathy, hereditary sensory and autonomic, type 2A variants (26 disease-causing).

Diseases related to Neuropathy, hereditary sensory and autonomic, type 2A

• Hereditary spastic paraplegia, also linked to KIF1A
• Amyotrophic lateral sclerosis, also linked to SCN9A
• Generalized epilepsy with febrile seizures plus, also linked to SCN9A
• Cardiac arrhythmia, also linked to SCN9A
• Neuropathy, hereditary sensory, type 2C, also linked to KIF1A
• Epilepsy, also linked to SCN9A
• Primary erythromelalgia, also linked to SCN9A
• Paroxysmal extreme pain disorder, also linked to SCN9A
• Focal epilepsy, also linked to SCN9A
• Channelopathy-associated congenital insensitivity to pain, also linked to SCN9A
• Autosomal recessive spastic paraplegia type 78, also linked to KIF1A
• Lennox-Gastaut syndrome, also linked to SCN9A

Frequently asked questions

Which genes are linked to Neuropathy, hereditary sensory and autonomic, type 2A?

In CATVariant, Neuropathy, hereditary sensory and autonomic, type 2A is linked to 2 analyzed proteins: SCN9A (Sodium channel protein type 9 subunit alpha) and KIF1A (Kinesin-like protein KIF1A).

How many genetic variants are linked to Neuropathy, hereditary sensory and autonomic, type 2A?

1,260 variants: 15 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,214 are of uncertain significance or have conflicting reports.

Which uncertain variants in Neuropathy, hereditary sensory and autonomic, type 2A look disease-causing?

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

Which variant effect predictor works best for Neuropathy, hereditary sensory and autonomic, type 2A?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.83, based on 14 disease-causing and 49 harmless variants).

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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