Is EGR2 p.Pro397His (c.1190C>A) pathogenic?

EGR2 p.Pro397His (c.1190C>A) is classified Conflicting classifications of pathogenicity in EGR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-30). AlphaMissense: likely pathogenic (0.9857); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1D.

What condition is associated with EGR2 p.Pro397His (c.1190C>A)?

EGR2 p.Pro397His (c.1190C>A) is associated with Charcot-Marie-Tooth disease type 1D (ClinVar).

How common is EGR2 p.Pro397His (c.1190C>A) in the general population?

EGR2 p.Pro397His (c.1190C>A) is absent from gnomAD v4.1 (gnomAD).

How is Charcot-Marie-Tooth disease type 1D inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EGR2 p.Pro397His (c.1190C>A)?

AlphaMissense predicts likely pathogenic (score 0.9857) — an in-silico prediction, not a clinical call.

EGR2 p.Pro397His

c.1190C>A · rs2492293699 · VCV2431049

Conflicting classifications of pathogenicity No assertion criteria

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9857 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 1D

Computational evidence

Protein change
AlphaMissense	0.9857	likely pathogenic · top 8% in EGR2
REVEL	0.542	indeterminate
SaProt	LLR -15.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 235 bp · p 2.4e-12 · regional, not allelic
Overall
CADD	33.0	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: EGR2
Protein: p.Pro397His
Coding: c.1190C>A
MANE Select: NM_000399
dbSNP: rs2492293699
Type: single nucleotide variant
Location: chr10:62813448 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.02

Full EGR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 1D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 1D (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

EGR2 p.Pro397= Likely benign ★ same residue
EGR2 p.Arg359Trp Pathogenic ★★ same condition
EGR2 p.Arg381Cys Pathogenic ★★ same condition
EGR2 p.Arg381His Pathogenic ★★ same condition
EGR2 p.Arg409Trp Pathogenic/Likely pathogenic ★★ same condition
EGR2 p.Glu412Gly Pathogenic/Likely pathogenic ★★ same condition
EGR2 p.Arg257Gln Uncertain significance ★★ ⚠ same condition
EGR2 c.169+10G>T Benign ★★ 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/egr2-p-pro397his (accessed [today's date]).

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