Is SCN2A p.Pro660Ser (c.1978C>T) pathogenic?

SCN2A p.Pro660Ser (c.1978C>T) is classified Uncertain significance in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-19). AlphaMissense: likely benign (0.0986); Very rare (popmax 0.000509%, nfe); Associated with seizures, benign familial infantile, 3.

What condition is associated with SCN2A p.Pro660Ser (c.1978C>T)?

SCN2A p.Pro660Ser (c.1978C>T) is associated with seizures, benign familial infantile, 3, developmental and epileptic encephalopathy, 11 (ClinVar).

How common is SCN2A p.Pro660Ser (c.1978C>T) in the general population?

SCN2A p.Pro660Ser (c.1978C>T) is very rare (popmax 0.000509%, 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.Pro660Ser (c.1978C>T)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

SCN2A p.Pro660Ser

c.1978C>T · rs1346341071 · VCV2931485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

seizures, benign familial infantile, 3

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -5.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,866 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,690 alleles · very rare exomes 4/1,461,562 · genomes 2/152,128 · 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.Pro660Ser
Coding: c.1978C>T
MANE Select: NM_001040142
dbSNP: rs1346341071
Type: single nucleotide variant
Location: chr2:165323462 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 660: 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)

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.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
SCN2A p.Lys156Gln 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-pro660ser (accessed [today's date]).

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