Is SCN2A p.Trp1424fs (c.4270dup) pathogenic?

SCN2A p.Trp1424fs (c.4270dup) is classified Pathogenic in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-07). Absent from gnomAD; Associated with developmental and epileptic encephalopathy, 11.

How common is SCN2A p.Trp1424fs (c.4270dup) in the general population?

SCN2A p.Trp1424fs (c.4270dup) is absent from gnomAD (gnomAD).

SCN2A p.Trp1424fs

Q: What condition is associated with SCN2A p.Trp1424fs (c.4270dup)?

SCN2A p.Trp1424fs (c.4270dup) is associated with developmental and epileptic encephalopathy, 11, seizures, benign familial infantile, 3 (ClinVar).

c.4270dup · rs1553461662 · VCV533497

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

developmental and epileptic encephalopathy, 11

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 haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 23 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.46	GERP -3.5

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SCN2A
Protein: p.Trp1424fs
Coding: c.4270dup
MANE Select: NM_001040142
dbSNP: rs1553461662
Type: Duplication
Location: chr2:165377611 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 1424: a UniProt-annotated variant site (found in a patient with intractable epilepsy and severe mental decline; likely pathogenic; non-conducting; loss of voltage-gated sodium channel activity; dominant-negative); a UniProt-annotated variant site (found in a patient with schizofrenia; uncertain significance); a UniProt-annotated variant site (found in a patient with autism spectrum disorder; likely pathogenic); a UniProt-annotated variant site (found in a patient with autism spectrum disorder; likely pathogenic; loss of voltage-gated sodium channel activity; non-conducting); a UniProt-annotated variant site (in dee11); an α-helix

Full SCN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: seizures, benign familial infantile, 3

Similar variants

SCN2A p.Trp1424Ter Pathogenic ★★ same residue
SCN2A p.Ser661fs Pathogenic ★★ same condition
SCN2A p.Ala466_Ala467dup Uncertain significance ★★ same condition
SCN2A p.Asn340fs Pathogenic ★ same condition
SCN2A p.Asn503fs Pathogenic ★ same condition
SCN2A p.Asn624fs Likely pathogenic ★ same condition
SCN2A p.Asp1070fs Pathogenic ★ same condition
SCN2A p.Asp1246fs 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/scn2a-p-trp1424fs (accessed [today's date]).

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