Is SCN2A p.Pro759= (c.2277A>G) pathogenic?

SCN2A p.Pro759= (c.2277A>G) is classified Likely benign in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). Very rare (popmax 8.48e-05%, nfe); Associated with seizures, benign familial infantile, 3.

What condition is associated with SCN2A p.Pro759= (c.2277A>G)?

SCN2A p.Pro759= (c.2277A>G) is associated with seizures, benign familial infantile, 3, developmental and epileptic encephalopathy, 11 (ClinVar).

How common is SCN2A p.Pro759= (c.2277A>G) in the general population?

SCN2A p.Pro759= (c.2277A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Self-limited neonatal-infantile epilepsy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

SCN2A p.Pro759=

c.2277A>G · rs1409376152 · VCV2926394

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

seizures, benign familial infantile, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.6	GERP -3.8
Overall
CADD	0.227	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,798 alleles

Overall 6.2e-05% 1/1,613,736 alleles · very rare exomes 0/1,461,592 · genomes 1/152,144 · 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: SCN2A
Protein: p.Pro759=
Coding: c.2277A>G
MANE Select: NM_001040142
dbSNP: rs1409376152
Type: single nucleotide variant
Location: chr2:165331457 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 759: 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 β-strand

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

Disease context

seizures, benign familial infantile, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 11

For Self-limited neonatal-infantile epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

SCN2A p.Pro759Thr Uncertain significance ★ ⚠ same residue
SCN2A p.Ala1773Thr Pathogenic ★★★ same condition
SCN2A p.Arg220Gly Likely pathogenic ★★★ same condition
SCN2A p.Arg853Gln Pathogenic ★★★ same condition
SCN2A p.Gly899Asp Likely pathogenic ★★★ same condition
SCN2A p.Leu1611Pro Pathogenic ★★★ same condition
SCN2A p.Leu886Ser Likely pathogenic ★★★ same condition
SCN2A p.Lys1260Glu 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/scn2a-p-pro759 (accessed [today's date]).

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