Is SCN2A p.Ala263Pro (c.787G>C) pathogenic?

SCN2A p.Ala263Pro (c.787G>C) is classified Uncertain significance in SCN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-18). AlphaMissense: likely pathogenic (0.996); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 11.

What condition is associated with SCN2A p.Ala263Pro (c.787G>C)?

SCN2A p.Ala263Pro (c.787G>C) is associated with developmental and epileptic encephalopathy, 11, seizures, benign familial infantile, 3, episodic ataxia, type 9 (ClinVar).

How common is SCN2A p.Ala263Pro (c.787G>C) in the general population?

SCN2A p.Ala263Pro (c.787G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN2A p.Ala263Pro (c.787G>C)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

SCN2A p.Ala263Pro

c.787G>C · rs1697364931 · VCV1013823

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.996 · 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	0.996	likely pathogenic · top 10% in SCN2A
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -14.93	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 2,558 bp · p 2.7e-21 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Ala263Pro
Coding: c.787G>C
MANE Select: NM_001040142
dbSNP: rs1697364931
Type: single nucleotide variant
Location: chr2:165310412 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 263: 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 (in dee11); a UniProt-annotated variant site (in dee11 and ea9; increased voltage-gated sodium channel activity; increased persistent sodium current; gain of function); 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 episodic ataxia, type 9 SCN2A-related disorder

Similar variants

SCN2A p.Ala263Val Pathogenic ★★ same residue
SCN2A p.Ala263Glu Likely pathogenic ★ same residue
SCN2A p.Ala263Gly Likely pathogenic ★ same residue
SCN2A p.Ala263Thr Pathogenic ★ same residue
SCN2A p.Ala263Ser Uncertain significance ★ ⚠ same residue
SCN2A p.Ala263= Likely benign ★ same residue
SCN2A p.Ala1773Thr Pathogenic ★★★ same condition
SCN2A p.Arg220Gly 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-ala263pro (accessed [today's date]).

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