Is SCN2A p.Ser495Cys (c.1484C>G) pathogenic?

SCN2A p.Ser495Cys (c.1484C>G) is classified Uncertain significance in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: ambiguous (0.3652); Very rare (popmax 0.00017%, nfe); Associated with seizures, benign familial infantile, 3.

What condition is associated with SCN2A p.Ser495Cys (c.1484C>G)?

SCN2A p.Ser495Cys (c.1484C>G) is associated with seizures, benign familial infantile, 3, developmental and epileptic encephalopathy, 11 (ClinVar).

How common is SCN2A p.Ser495Cys (c.1484C>G) in the general population?

SCN2A p.Ser495Cys (c.1484C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Self-limited neonatal-infantile epilepsy inherited?

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

What do computational predictors say about SCN2A p.Ser495Cys (c.1484C>G)?

AlphaMissense predicts ambiguous (score 0.3652) — an in-silico prediction, not a clinical call.

SCN2A p.Ser495Cys

c.1484C>G · rs140661535 · VCV410981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

seizures, benign familial infantile, 3

Computational evidence

Protein change
AlphaMissense	0.3652	ambiguous
REVEL	0.733	pathogenic-leaning
SaProt	LLR -9.13	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 17 kb · p 0.00027 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,798 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,314 alleles · very rare exomes 2/1,461,770 · genomes 0/151,544 · 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.Ser495Cys
Coding: c.1484C>G
MANE Select: NM_001040142
dbSNP: rs140661535
Type: single nucleotide variant
Location: chr2:165315571 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 495: 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); the 'disordered' region

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.Ser495Tyr Uncertain significance ★ ⚠ same residue
SCN2A p.Ser495= Likely benign ★ 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

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-ser495cys (accessed [today's date]).

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