EN2

Chr 7

engrailed homeobox 2

NCBI Gene: 2020ENSG00000164778UniProt: P19622

Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the 'engrailed' (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system. [provided by RefSeq, Jul 2008]

170
ClinVar variants
81
Pathogenic / LP
0.63
pLI score
0
Active trials
Clinical Summary— EN2
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
81 Pathogenic / Likely Pathogenic· 82 VUS of 170 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.63LOEUF
pLI 0.634
Z-score 2.20
OE 0.13 (0.05–0.63)
Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.08Z-score
OE missense 0.72 (0.61–0.86)
88 obs / 121.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.05–0.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.61–0.86)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 1 / 7.5Missense obs/exp: 88 / 121.6Syn Z: -0.23

ClinVar Variant Classifications

170 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74
Likely Pathogenic7
VUS82
Likely Benign3
Benign4
74
Pathogenic
7
Likely Pathogenic
82
VUS
3
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
74
0
74
Likely Pathogenic
0
0
7
0
7
VUS
0
74
8
0
82
Likely Benign
0
2
0
1
3
Benign
0
0
0
4
4
Total076895170

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

View in ClinVar →

Protein Context — Lollipop Plot

EN2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ENGRAILED 2; EN2
MIM #131310 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
EN2 as an oncogene promotes tumor progression via regulating CCL20 in colorectal cancer.
Li Y et al.·Cell Death Dis
2020
Hypermethylation of PDX1, EN2, and MSX1 predicts the prognosis of colorectal cancer.
Lee Y et al.·Exp Mol Med
2022
A novel super-enhancer-driven lncRNA LINC00973 governs head and neck squamous cell carcinoma progression through EN2.
Wang A et al.·Cell Death Dis
2025
Is Engrailed-2 (EN2) a truly promising biomarker in prostate cancer detection?
Do Carmo Silva J et al.·Biomarkers
2020
Circ_0071589 contributes to growth, angiogenesis, and metastasis of colorectal cancer through regulating miR-296-5p/EN2 axis.
Tang S et al.·J Biochem Mol Toxicol
2023
Search for genes involved in Joubert syndrome: evidence that one or more major loci are yet to be identified and exclusion of candidate genes EN1, EN2, FGF8, and BARHL1.
Blair IP et al.·Am J Med Genet
2002
Encoding Enhanced Complex CNN for Accurate and Highly Accelerated MRI.
Li Z et al.·IEEE Trans Med Imaging
2024
Engrailed-2 (EN2) protein in cervical mucus: a novel biomarker for endometrial carcinoma.
Wang T et al.·Clin Transl Oncol
2025
Immunohistochemistry Biomarkers in Nonmuscle Invasive Bladder Cancer.
Ranzi AD et al.·Appl Immunohistochem Mol Morphol
2017
Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder.
Hnoonual A et al.·Psychiatr Genet
2016Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools