Is SCN8A p.Ser132Pro (c.394T>C) pathogenic?

SCN8A p.Ser132Pro (c.394T>C) is classified Uncertain significance in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). AlphaMissense: likely pathogenic (0.8281); No allele count reported in gnomAD v4.1 (AN 1,426,532); Associated with early-infantile DEE.

What condition is associated with SCN8A p.Ser132Pro (c.394T>C)?

SCN8A p.Ser132Pro (c.394T>C) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Ser132Pro (c.394T>C) in the general population?

SCN8A p.Ser132Pro (c.394T>C) is no allele count reported in gnomAD v4.1 (AN 1,426,532) (gnomAD).

What do computational predictors say about SCN8A p.Ser132Pro (c.394T>C)?

AlphaMissense predicts likely pathogenic (score 0.8281) — an in-silico prediction, not a clinical call.

SCN8A p.Ser132Pro

c.394T>C · rs1449264729 · VCV1958781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8281 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,426,532)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.8281	likely pathogenic
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -1.70	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
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 0.24	constrained · MANE · 37 kb · p 1e-36 · regional, not allelic
Overall
CADD	25.6	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

No allele count reported in gnomAD v4.1 (AN 1,426,532). 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: SCN8A
Protein: p.Ser132Pro
Coding: c.394T>C
MANE Select: NM_001330260
dbSNP: rs1449264729
Type: single nucleotide variant
Location: chr12:51684291 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 132: 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.Ser132= Conflicting classifications of pathogenicity ★ 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-ser132pro (accessed [today's date]).

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