Is SCN4A p.Ala331Val (c.992C>T) pathogenic?

SCN4A p.Ala331Val (c.992C>T) is classified Uncertain significance in SCN4A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely benign (0.0872); Very rare (popmax 0.00102%, nfe); Associated with hyperkalemic periodic paralysis.

What condition is associated with SCN4A p.Ala331Val (c.992C>T)?

SCN4A p.Ala331Val (c.992C>T) is associated with hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Ala331Val (c.992C>T) in the general population?

SCN4A p.Ala331Val (c.992C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

How is Hyperkalemic periodic paralysis inherited?

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

What do computational predictors say about SCN4A p.Ala331Val (c.992C>T)?

AlphaMissense predicts likely benign (score 0.0872) — an in-silico prediction, not a clinical call.

SCN4A p.Ala331Val

c.992C>T · rs368831487 · VCV2987718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0872 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyperkalemic periodic paralysis

Computational evidence

Protein change
AlphaMissense	0.0872	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.83, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 7.8e-08 · regional, not allelic
Overall
CADD	14.65	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,904 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,613,858 alleles · very rare exomes 11/1,461,702 · genomes 1/152,156 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SCN4A
Protein: p.Ala331Val
Coding: c.992C>T
MANE Select: NM_000334
dbSNP: rs368831487
Type: single nucleotide variant
Location: chr17:63968067 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.09 · 3 PDB

Full SCN4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperkalemic periodic paralysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperkalemic periodic paralysis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

SCN4A c.1037-1G>A Pathogenic/Likely pathogenic ★★ same condition
SCN4A p.Arg1132Gln Pathogenic ★★ same condition
SCN4A p.Arg222Gln Pathogenic/Likely pathogenic ★★ same condition
SCN4A p.Arg222Trp Pathogenic/Likely pathogenic ★★ same condition
SCN4A p.Arg669His Pathogenic ★★ same condition
SCN4A p.Arg672Cys Pathogenic ★★ same condition
SCN4A p.Arg672Gly Pathogenic ★★ same condition
SCN4A p.Arg672His 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/scn4a-p-ala331val (accessed [today's date]).

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