Is SCN8A p.Val409Ala (c.1226T>C) pathogenic?

SCN8A p.Val409Ala (c.1226T>C) is classified Pathogenic/Likely pathogenic in SCN8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-13). AlphaMissense: likely pathogenic (0.9716); Absent from gnomAD v4.1; Associated with cognitive impairment with or without cerebellar ataxia.

What condition is associated with SCN8A p.Val409Ala (c.1226T>C)?

SCN8A p.Val409Ala (c.1226T>C) is associated with cognitive impairment with or without cerebellar ataxia, early-infantile DEE (ClinVar).

How common is SCN8A p.Val409Ala (c.1226T>C) in the general population?

SCN8A p.Val409Ala (c.1226T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Val409Ala (c.1226T>C)?

AlphaMissense predicts likely pathogenic (score 0.9716) — an in-silico prediction, not a clinical call.

SCN8A p.Val409Ala

c.1226T>C · rs2138748239 · VCV1385042

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9716 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cognitive impairment with or without cerebellar ataxia

Computational evidence

Protein change
AlphaMissense	0.9716	likely pathogenic ✓ concordant with ClinVar
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -15.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.18	constrained · MANE · 4,449 bp · p 9.4e-24 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SCN8A
Protein: p.Val409Ala
Coding: c.1226T>C
MANE Select: NM_001330260
dbSNP: rs2138748239
Type: single nucleotide variant
Location: chr12:51705508 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 409: an α-helix

Full SCN8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cognitive impairment with or without cerebellar ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: early-infantile DEE

Similar variants

SCN8A p.Val409Leu Likely pathogenic same residue
SCN8A c.615-1G>A Pathogenic ★★★ same condition
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same condition
SCN8A p.Asn418Asp Likely pathogenic ★★★ same condition
SCN8A p.Glu1218Lys Pathogenic ★★★ same condition
SCN8A p.Ile1631Thr Likely pathogenic ★★★ same condition
SCN8A p.Ser845Cys Likely pathogenic ★★★ ⚠ same condition
SCN8A p.Ser845Phe Likely 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/scn8a-p-val409ala (accessed [today's date]).

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