Is SCN8A p.Pro474Ser (c.1420C>T) pathogenic?

SCN8A p.Pro474Ser (c.1420C>T) is classified Uncertain significance in SCN8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-04). AlphaMissense: likely benign (0.069); Very rare (popmax 0.00017%, nfe); Associated with early-infantile DEE.

How common is SCN8A p.Pro474Ser (c.1420C>T) in the general population?

SCN8A p.Pro474Ser (c.1420C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SCN8A p.Pro474Ser (c.1420C>T)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

SCN8A p.Pro474Ser

Q: What condition is associated with SCN8A p.Pro474Ser (c.1420C>T)?

SCN8A p.Pro474Ser (c.1420C>T) is associated with early-infantile DEE, cognitive impairment with or without cerebellar ataxia, developmental and epileptic encephalopathy, 13 (ClinVar).

c.1420C>T · rs1160066733 · VCV1406186

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -4.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.049, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 46 kb · p 0.00057 · regional, not allelic
Overall
CADD	19.68	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 0.00017% European (non-Finnish) · 2/1,175,814 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,605,014 alleles · very rare exomes 2/1,452,744 · genomes 0/152,270 · 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.Pro474Ser
Coding: c.1420C>T
MANE Select: NM_001330260
dbSNP: rs1160066733
Type: single nucleotide variant
Location: chr12:51706500 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 474: the 'disordered' region

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

Also linked: cognitive impairment with or without cerebellar ataxia developmental and epileptic encephalopathy, 13 seizures, benign familial infantile, 5 myoclonus, familial, 2

Similar variants

SCN8A p.Pro474Arg Uncertain significance ★ ⚠ same residue
SCN8A p.Pro474Leu Uncertain significance ★ ⚠ same residue
SCN8A c.615-1G>A Pathogenic ★★★ same condition
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same condition
SCN8A p.Asn1318Ser Likely pathogenic ★★★ same condition
SCN8A p.Asn418Asp Likely pathogenic ★★★ same condition
SCN8A p.Glu1218Lys Pathogenic ★★★ same condition
SCN8A p.Ile1631Thr 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-pro474ser (accessed [today's date]).

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