Is SCN2A p.Phe262Ser (c.785T>C) pathogenic?

SCN2A p.Phe262Ser (c.785T>C) is classified Pathogenic/Likely pathogenic in SCN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-16). AlphaMissense: likely pathogenic (0.9939); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 11.

What condition is associated with SCN2A p.Phe262Ser (c.785T>C)?

SCN2A p.Phe262Ser (c.785T>C) is associated with developmental and epileptic encephalopathy, 11 (ClinVar).

How common is SCN2A p.Phe262Ser (c.785T>C) in the general population?

SCN2A p.Phe262Ser (c.785T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN2A p.Phe262Ser (c.785T>C)?

AlphaMissense predicts likely pathogenic (score 0.9939) — an in-silico prediction, not a clinical call.

SCN2A p.Phe262Ser

c.785T>C · rs1697364805 · VCV982024

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9939 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 11

Computational evidence

Protein change
AlphaMissense	0.9939	likely pathogenic ✓ concordant with ClinVar
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -16.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 2,558 bp · p 2.7e-21 · regional, not allelic
Overall
CADD	27.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SCN2A
Protein: p.Phe262Ser
Coding: c.785T>C
MANE Select: NM_001040142
dbSNP: rs1697364805
Type: single nucleotide variant
Location: chr2:165310410 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 262: 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); 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

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-phe262ser (accessed [today's date]).

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