Is SCN8A p.Ile652Phe (c.1954A>T) pathogenic?

SCN8A p.Ile652Phe (c.1954A>T) is classified Uncertain significance in SCN8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-25). AlphaMissense: likely benign (0.3182); Very rare (popmax 0.00133%, afr); Associated with early-infantile DEE.

What condition is associated with SCN8A p.Ile652Phe (c.1954A>T)?

SCN8A p.Ile652Phe (c.1954A>T) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Ile652Phe (c.1954A>T) in the general population?

SCN8A p.Ile652Phe (c.1954A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SCN8A p.Ile652Phe (c.1954A>T)?

AlphaMissense predicts likely benign (score 0.3182) — an in-silico prediction, not a clinical call.

SCN8A p.Ile652Phe

c.1954A>T · rs1048609401 · VCV2174191

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.3182	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -3.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 46 kb · p 0.00057 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00133% African / African-American · 1/74,936 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,602,574 alleles · very rare exomes 2/1,450,348 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,936
European (non-Finnish)	0.00017%	589,911

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.Ile652Phe
Coding: c.1954A>T
MANE Select: NM_001330260
dbSNP: rs1048609401
Type: single nucleotide variant
Location: chr12:51721864 (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.Ile652Val 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-ile652phe (accessed [today's date]).

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