EGR2

Chr 10ADAR

early growth response 2

Also known as: AT591, CMT1D, CMT4E, KROX20

NCBI Gene: 1959 ENSG00000122877 UniProt: P11161 OMIM: 129010

This transcription factor contains three tandem C2H2-type zinc fingers and regulates myelination in peripheral nerves. Mutations cause Charcot-Marie-Tooth disease types 1D and 4E, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy type 1, with inheritance patterns that are autosomal dominant or autosomal recessive depending on the specific mutation. The pathogenic mechanism involves loss of function, leading to defective peripheral nerve myelination.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a transcription factor with three tandem C2H2-type zinc fingers. Defects in this gene are associated with Charcot-Marie-Tooth disease type 1D (CMT1D), Charcot-Marie-Tooth disease type 4E (CMT4E), and with Dejerine-Sottas syndrome (DSS). Multiple transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.603 OMIM phenotypes

Clinical Summary— EGR2

🧬

Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.50) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

19 unique Pathogenic / Likely Pathogenic· 274 VUS of 466 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — EGR2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.503

Z-score 2.42

OE 0.19 (0.08–0.60)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

2.44Z-score

OE missense 0.60 (0.53–0.68)

175 obs / 292.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.08–0.60)

0≤0.351.4

Missense OE?0.60 (0.53–0.68)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 2 / 10.4Missense obs/exp: 175 / 292.6Syn Z: -0.58

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEGR2-related neuropathy, congenital hypomyelinatingLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.5575th %ile

GOF

0.3986th %ile

LOF

0.76top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNWe also contrast morphological studies in the context of the I268N homozygous recessive mutation affecting the NAB repressor binding site and the R359W dominant-negative mutation in the zinc-finger domain.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 17717711 ↗

ClinVar Variant Classifications

466 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic6

VUS274

Likely Benign138

Benign15

Conflicting18

Pathogenic

Likely Pathogenic

274

VUS

138

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	13	0	0	13
Likely Pathogenic	0	6	0	0	6
VUS	11	249	14	0	274
Likely Benign	0	3	16	119	138
Benign	0	0	14	1	15
Conflicting	—				18
Total	11	271	44	120	464

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

15 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap EGR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →