Is SCN8A p.Val784Ile (c.2350G>A) pathogenic?

SCN8A p.Val784Ile (c.2350G>A) is classified Uncertain significance in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-02). AlphaMissense: likely benign (0.168); Absent from gnomAD v4.1; Associated with early-infantile DEE.

What condition is associated with SCN8A p.Val784Ile (c.2350G>A)?

SCN8A p.Val784Ile (c.2350G>A) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Val784Ile (c.2350G>A) in the general population?

SCN8A p.Val784Ile (c.2350G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Val784Ile (c.2350G>A)?

AlphaMissense predicts likely benign (score 0.168) — an in-silico prediction, not a clinical call.

SCN8A p.Val784Ile

c.2350G>A · rs1942596077 · VCV1445748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.168 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.168	likely benign
REVEL	0.506	indeterminate
SaProt	LLR -5.93	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 17 kb · p 8.5e-44 · regional, not allelic
Overall
CADD	24.6	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

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.Val784Ile
Coding: c.2350G>A
MANE Select: NM_001330260
dbSNP: rs1942596077
Type: single nucleotide variant
Location: chr12:51751573 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 784: an α-helix

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

Disease context

early-infantile DEE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SCN8A p.Val784= Likely benign ★ 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-val784ile (accessed [today's date]).

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