Is SCN8A p.Arg1872Pro (c.5615G>C) pathogenic?

SCN8A p.Arg1872Pro (c.5615G>C) is classified Likely pathogenic in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.9974); Absent from gnomAD v4.1; Associated with epilepsy.

What condition is associated with SCN8A p.Arg1872Pro (c.5615G>C)?

SCN8A p.Arg1872Pro (c.5615G>C) is associated with epilepsy (ClinVar).

How common is SCN8A p.Arg1872Pro (c.5615G>C) in the general population?

SCN8A p.Arg1872Pro (c.5615G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Arg1872Pro (c.5615G>C)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

SCN8A p.Arg1872Pro

c.5615G>C · VCV4871762

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic ✓ concordant with ClinVar · top 8% in SCN8A
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -12.70	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 2.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 327 bp · p 0.00014 · regional, not allelic
Overall
CADD	28.1	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

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.Arg1872Pro
Coding: c.5615G>C
MANE Select: NM_001330260
Type: single nucleotide variant
Location: chr12:51807101 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 1872: a UniProt-annotated variant site (in dee13; gain-of-function mutation; increased voltage-gated sodium channel activity; impaired channel inactivation); a UniProt-annotated variant site (in dee13; gain-of-function mutation; increased voltage-gated sodium channel activity; impaired channel inactivation; no effect on interactions with fgf14, scn1b, gnb2 and gng3)

Full SCN8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same residue
SCN8A p.Arg1872Leu Pathogenic ★★ same residue
SCN8A p.Arg1872Trp Pathogenic ★★ same residue
SCN8A p.Arg1872Gly Pathogenic ★ same residue
SCN8A p.Glu1483Lys Pathogenic ★★ same condition
SCN8A p.Met1529Val Pathogenic/Likely pathogenic ★★ same condition
SCN8A p.Phe356Tyr Likely pathogenic ★ same condition
SCN8A c.615-1G>A Pathogenic ★★★ same type

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-arg1872pro (accessed [today's date]).

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