Is SCN2A p.Arg2001fs (c.5992_5999dup) pathogenic?

SCN2A p.Arg2001fs (c.59925999dup) is classified Uncertain significance in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-05). Associated with developmental and epileptic encephalopathy, 11.

What condition is associated with SCN2A p.Arg2001fs (c.5992_5999dup)?

SCN2A p.Arg2001fs (c.5992_5999dup) is associated with developmental and epileptic encephalopathy, 11, seizures, benign familial infantile, 3 (ClinVar).

SCN2A p.Arg2001fs

c.5992_5999dup · VCV3754789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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	escapes	premature termination codon in the last exon (27 of 27) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.083	GERP -2.3, phastCons 0.092
Region caveats
Repeat context	tandem	A-rich low complexity · ambiguous alignment · confidence, not pathogenicity

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

Variant & gene context

Gene: SCN2A
Protein: p.Arg2001fs
Coding: c.5992_5999dup
MANE Select: NM_001040142
Type: Duplication
Location: chr2:165389797 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 2001: 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); the 'disordered' region

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.Arg2001Lys Uncertain significance ★ ⚠ 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-arg2001fs (accessed [today's date]).

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