Is SCN8A p.Phe104fs (c.309_310del) pathogenic?

SCN8A p.Phe104fs (c.309310del) is classified Likely pathogenic in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-03). Very rare (popmax 8.58e-05%, nfe); Associated with SCN8A-related disorder.

What condition is associated with SCN8A p.Phe104fs (c.309_310del)?

SCN8A p.Phe104fs (c.309_310del) is associated with SCN8A-related disorder (ClinVar).

How common is SCN8A p.Phe104fs (c.309_310del) in the general population?

SCN8A p.Phe104fs (c.309_310del) is very rare (popmax 8.58e-05%, nfe) (gnomAD).

SCN8A p.Phe104fs

c.309_310del · VCV4916823

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.58e-05%, nfe)

Conditions

SCN8A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 3 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.4	GERP 0.74, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.58e-05% European (non-Finnish) · 1/1,166,008 alleles

Overall 6.26e-05% 1/1,598,600 alleles · very rare exomes 1/1,446,408 · genomes 0/152,192 · joint denominator

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.Phe104fs
Coding: c.309_310del
MANE Select: NM_001330260
Type: Microsatellite
Location: chr12:51684202 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 104: a β-strand

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

Disease context

SCN8A-related disorder

Similar variants

SCN8A p.Phe1746del Uncertain significance ★★ same condition
SCN8A p.Phe391del Uncertain significance same condition
SCN8A c.-70CGC[3] Likely benign same condition
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

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-phe104fs (accessed [today's date]).

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