Is SCN9A p.Val331= (c.993G>T) pathogenic?

SCN9A p.Val331= (c.993G>T) is classified Uncertain significance in SCN9A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-02). No allele count reported in gnomAD v4.1 (AN 1,609,568); Associated with neuropathy, hereditary sensory and autonomic, type 2A.

What condition is associated with SCN9A p.Val331= (c.993G>T)?

SCN9A p.Val331= (c.993G>T) is associated with neuropathy, hereditary sensory and autonomic, type 2A, generalized epilepsy with febrile seizures plus, type 7 (ClinVar).

How common is SCN9A p.Val331= (c.993G>T) in the general population?

SCN9A p.Val331= (c.993G>T) is no allele count reported in gnomAD v4.1 (AN 1,609,568) (gnomAD).

SCN9A p.Val331=

Q: How is Hereditary sensory and autonomic neuropathy type 2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.993G>T · rs2468067388 · VCV2954386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,609,568)

Conditions

neuropathy, hereditary sensory and autonomic, type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.20	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1.1	GERP -0.18, phastCons 0.5
Overall
CADD	2.148	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,609,568). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SCN9A
Protein: p.Val331=
Coding: c.993G>T
MANE Select: NM_001365536
dbSNP: rs2468067388
Type: single nucleotide variant
Location: chr2:166293345 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.53 · 44 PDB
Residue 331: a β-strand

Full SCN9A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuropathy, hereditary sensory and autonomic, type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: generalized epilepsy with febrile seizures plus, type 7

For Hereditary sensory and autonomic neuropathy type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SCN9A c.258+1G>A Pathogenic/Likely pathogenic ★★ same condition
SCN9A c.378-1C>T Likely pathogenic ★★ same condition
SCN9A p.Arg1499Ter Pathogenic ★★ same condition
SCN9A p.Arg1619Ter Pathogenic/Likely pathogenic ★★ same condition
SCN9A p.Arg277Ter Pathogenic/Likely pathogenic ★★ same condition
SCN9A p.Arg841Ter Pathogenic/Likely pathogenic ★★ same condition
SCN9A p.Arg907Gln Pathogenic/Likely pathogenic ★★ same condition
SCN9A p.Trp1332Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/scn9a-p-val331 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown