Is SCN8A p.Val960Phe (c.2878G>T) pathogenic?

SCN8A p.Val960Phe (c.2878G>T) is classified Uncertain significance in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-29). AlphaMissense: likely pathogenic (0.9625); Absent from gnomAD v4.1.

How common is SCN8A p.Val960Phe (c.2878G>T) in the general population?

SCN8A p.Val960Phe (c.2878G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Val960Phe (c.2878G>T)?

AlphaMissense predicts likely pathogenic (score 0.9625) — an in-silico prediction, not a clinical call.

SCN8A p.Val960Phe

c.2878G>T · VCV4916847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9625 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9625	likely pathogenic
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -14.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 17 kb · p 8.5e-44 · regional, not allelic
Overall
CADD	26.8	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.Val960Phe
Coding: c.2878G>T
MANE Select: NM_001330260
Type: single nucleotide variant
Location: chr12:51766004 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 960: a UniProt-annotated variant site (in dee13; uncertain significance); an α-helix

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

Similar variants

SCN8A p.Val960Asp Pathogenic ★ same residue
SCN8A p.Val960= Likely benign ★ same residue
SCN8A c.615-1G>A Pathogenic ★★★ same type
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same type
SCN8A p.Asn1318Ser Likely pathogenic ★★★ same type
SCN8A p.Asn418Asp Likely pathogenic ★★★ same type
SCN8A p.Glu1218Lys Pathogenic ★★★ same type
SCN8A p.Ile1631Thr Likely 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-val960phe (accessed [today's date]).

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