Is SCN8A p.Ala798Val (c.2393C>T) pathogenic?

SCN8A p.Ala798Val (c.2393C>T) is classified Uncertain significance in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.2583); Very rare (popmax 8.48e-05%, nfe); Associated with early-infantile DEE.

What condition is associated with SCN8A p.Ala798Val (c.2393C>T)?

SCN8A p.Ala798Val (c.2393C>T) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Ala798Val (c.2393C>T) in the general population?

SCN8A p.Ala798Val (c.2393C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SCN8A p.Ala798Val (c.2393C>T)?

AlphaMissense predicts likely benign (score 0.2583) — an in-silico prediction, not a clinical call.

SCN8A p.Ala798Val

c.2393C>T · rs1650809067 · VCV2193734

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.2583	likely benign
REVEL	0.721	pathogenic-leaning
SaProt	LLR -8.83	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 17 kb · p 8.5e-44 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,658 alleles

Overall 6.2e-05% 1/1,613,418 alleles · very rare exomes 1/1,461,164 · genomes 0/152,254 · 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: SCN8A
Protein: p.Ala798Val
Coding: c.2393C>T
MANE Select: NM_001330260
dbSNP: rs1650809067
Type: single nucleotide variant
Location: chr12:51762525 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 798: 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.Ala798= Benign/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-ala798val (accessed [today's date]).

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