Is SCN8A p.Pro1503Ser (c.4507C>T) pathogenic?

SCN8A p.Pro1503Ser (c.4507C>T) is classified Uncertain significance in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely pathogenic (0.9756); Absent from gnomAD v4.1; Associated with SCN8A-related disorder.

What condition is associated with SCN8A p.Pro1503Ser (c.4507C>T)?

SCN8A p.Pro1503Ser (c.4507C>T) is associated with SCN8A-related disorder (ClinVar).

How common is SCN8A p.Pro1503Ser (c.4507C>T) in the general population?

SCN8A p.Pro1503Ser (c.4507C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Pro1503Ser (c.4507C>T)?

AlphaMissense predicts likely pathogenic (score 0.9756) — an in-silico prediction, not a clinical call.

SCN8A p.Pro1503Ser

c.4507C>T · VCV4293368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9756 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SCN8A-related disorder

Computational evidence

Protein change
AlphaMissense	0.9756	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -11.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.17	constrained · MANE · 7,767 bp · p 3.9e-34 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Pro1503Ser
Coding: c.4507C>T
MANE Select: NM_001330260
Type: single nucleotide variant
Location: chr12:51790485 (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

SCN8A-related disorder

Similar variants

SCN8A p.Pro1503= Benign ★★ same residue
SCN8A p.Ala1323Thr Pathogenic/Likely pathogenic ★★ same condition
SCN8A p.Ala874Thr Pathogenic/Likely pathogenic ★★ same condition
SCN8A p.Arg847Ter Pathogenic/Likely pathogenic ★★ same condition
SCN8A p.Arg850Gly Pathogenic/Likely pathogenic ★★ same condition
SCN8A p.Arg850Ter Pathogenic/Likely pathogenic ★★ same condition
SCN8A p.Arg931Gln Likely pathogenic ★★ same condition
SCN8A p.Ile142Val Pathogenic/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-pro1503ser (accessed [today's date]).

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