Is SCN8A p.Arg844Pro (c.2531G>C) pathogenic?

SCN8A p.Arg844Pro (c.2531G>C) is classified Uncertain significance in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: likely pathogenic (0.9972); Absent from gnomAD v4.1; Associated with SCN8A-related disorder.

What condition is associated with SCN8A p.Arg844Pro (c.2531G>C)?

SCN8A p.Arg844Pro (c.2531G>C) is associated with SCN8A-related disorder (ClinVar).

How common is SCN8A p.Arg844Pro (c.2531G>C) in the general population?

SCN8A p.Arg844Pro (c.2531G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Arg844Pro (c.2531G>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

SCN8A p.Arg844Pro

c.2531G>C · rs1476532344 · VCV2628402

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9972 · 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	0.9972	likely pathogenic · top 8% in SCN8A
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -14.04	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 17 kb · p 8.5e-44 · regional, not allelic
Overall
CADD	32.0	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.Arg844Pro
Coding: c.2531G>C
MANE Select: NM_001330260
dbSNP: rs1476532344
Type: single nucleotide variant
Location: chr12:51762663 (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.Arg844Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN8A p.Arg844Ter Uncertain significance ★ 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

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-arg844pro (accessed [today's date]).

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