Is SCN2A p.Ser877= (c.2631T>C) pathogenic?

SCN2A p.Ser877= (c.2631T>C) is classified Conflicting classifications of pathogenicity in SCN2A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-28). Very rare (popmax 0.000339%, nfe); Associated with developmental and epileptic encephalopathy, 11.

What condition is associated with SCN2A p.Ser877= (c.2631T>C)?

SCN2A p.Ser877= (c.2631T>C) is associated with developmental and epileptic encephalopathy, 11, seizures, benign familial infantile, 3 (ClinVar).

How common is SCN2A p.Ser877= (c.2631T>C) in the general population?

SCN2A p.Ser877= (c.2631T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

SCN2A p.Ser877=

c.2631T>C · rs1292645984 · VCV593306

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

developmental and epileptic encephalopathy, 11

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 -15	GERP -3.8
Overall
CADD	0.053	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,036 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,064 alleles · very rare exomes 1/1,461,882 · genomes 3/152,182 · 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.Ser877=
Coding: c.2631T>C
MANE Select: NM_001040142
dbSNP: rs1292645984
Type: single nucleotide variant
Location: chr2:165344623 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 877: 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); an α-helix

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.Ser877Ala 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-ser877 (accessed [today's date]).

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