Is SCN2A p.Phe207Cys (c.620T>G) pathogenic?

SCN2A p.Phe207Cys (c.620T>G) is classified Likely pathogenic in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-05). AlphaMissense: likely pathogenic (0.9376); Absent from gnomAD v4.1.

How common is SCN2A p.Phe207Cys (c.620T>G) in the general population?

SCN2A p.Phe207Cys (c.620T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN2A p.Phe207Cys (c.620T>G)?

AlphaMissense predicts likely pathogenic (score 0.9376) — an in-silico prediction, not a clinical call.

SCN2A p.Phe207Cys

c.620T>G · rs1064796691 · VCV423904

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9376 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9376	likely pathogenic ✓ concordant with ClinVar
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -14.44	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	28.3	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.Phe207Cys
Coding: c.620T>G
MANE Select: NM_001040142
dbSNP: rs1064796691
Type: single nucleotide variant
Location: chr2:165309366 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 207: 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 β-strand

Full SCN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SCN2A p.Phe207Ser Likely pathogenic ★★ same residue
SCN2A p.Ala1773Thr Pathogenic ★★★ same type
SCN2A p.Arg220Gly Likely pathogenic ★★★ same type
SCN2A p.Arg853Gln Pathogenic ★★★ same type
SCN2A p.Gly899Asp Likely pathogenic ★★★ same type
SCN2A p.Leu1611Pro Pathogenic ★★★ same type
SCN2A p.Leu886Ser Likely pathogenic ★★★ same type
SCN2A p.Lys1260Gln Likely pathogenic ★★★ same type

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-phe207cys (accessed [today's date]).

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