Is SCN8A p.Pro604Ser (c.1810C>T) pathogenic?

SCN8A p.Pro604Ser (c.1810C>T) is classified Likely benign in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-10). AlphaMissense: likely pathogenic (0.5943); Very rare (popmax 0.00361%, amr); Associated with early-infantile DEE.

What condition is associated with SCN8A p.Pro604Ser (c.1810C>T)?

SCN8A p.Pro604Ser (c.1810C>T) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Pro604Ser (c.1810C>T) in the general population?

SCN8A p.Pro604Ser (c.1810C>T) is very rare (popmax 0.00361%, amr) (gnomAD).

What do computational predictors say about SCN8A p.Pro604Ser (c.1810C>T)?

AlphaMissense predicts likely pathogenic (score 0.5943) — an in-silico prediction, not a clinical call.

SCN8A p.Pro604Ser

c.1810C>T · rs1285097368 · VCV700958

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00361%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.5943	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -5.93	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 46 kb · p 0.00057 · 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

Grpmax group 0.00361% Admixed American · 2/55,462 alleles

Filtering AF 0.000598% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000224%

Overall 0.000188% 3/1,592,620 alleles · very rare exomes 3/1,440,274 · genomes 0/152,346 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00361%	27,731
South Asian	0.00112%	88,922

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.Pro604Ser
Coding: c.1810C>T
MANE Select: NM_001330260
dbSNP: rs1285097368
Type: single nucleotide variant
Location: chr12:51721720 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB

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.Pro604Thr Uncertain significance ★ ⚠ 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-pro604ser (accessed [today's date]).

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