Is SCN2A p.Pro1041= (c.3123G>A) pathogenic?

SCN2A p.Pro1041= (c.3123G>A) is classified Benign/Likely benign in SCN2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.103%, afr); Associated with seizures, benign familial infantile, 3.

What condition is associated with SCN2A p.Pro1041= (c.3123G>A)?

SCN2A p.Pro1041= (c.3123G>A) is associated with seizures, benign familial infantile, 3, developmental and epileptic encephalopathy, 11, SCN2A-related disorder (ClinVar).

How common is SCN2A p.Pro1041= (c.3123G>A) in the general population?

SCN2A p.Pro1041= (c.3123G>A) is rare (popmax 0.103%, afr) (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.Pro1041=

c.3123G>A · rs147576541 · VCV331731

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.103%, afr)

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 -0.13	GERP -3.8, phastCons 0.63
Overall
CADD	9.211	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% African / African-American · 77/75,010 alleles

Filtering AF 0.0841% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0774%

Overall 0.00898% 145/1,613,900 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.103%	974
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0128%	7,813
Admixed American	0.01%	10,001
South Asian	0.00659%	15,177
European (non-Finnish)	0.00347%	28,778
East Asian	0.00223%	44,860

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.Pro1041=
Coding: c.3123G>A
MANE Select: NM_001040142
dbSNP: rs147576541
Type: single nucleotide variant
Location: chr2:165354395 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 1041: 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)

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 SCN2A-related disorder

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

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

SCN2A p.Pro1041Leu Pathogenic ★ ⚠ 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-pro1041 (accessed [today's date]).

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