EDN1

Chr 6ARAD

endothelin 1

Also known as: ARCND3, ET1, HDLCQ7, PPET1, QME

NCBI Gene: 1906ENSG00000078401UniProt: P05305

This gene encodes a preproprotein that is proteolytically processed to generate a secreted peptide that belongs to the endothelin/sarafotoxin family. This peptide is a potent vasoconstrictor and its cognate receptors are therapeutic targets in the treatment of pulmonary arterial hypertension. Aberrant expression of this gene may promote tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

Auriculocondylar syndrome 3MIM #615706
AR
Question mark ears, isolatedMIM #612798
AD
94
ClinVar variants
29
Pathogenic / LP
0.46
pLI score
2
Active trials
Clinical Summary— EDN1
🧬
Gene-Disease Validity (ClinGen)
auriculocondylar syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.
📋
ClinVar Variants
29 Pathogenic / Likely Pathogenic· 38 VUS of 94 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.64LOEUF
pLI 0.455
Z-score 2.33
OE 0.20 (0.08–0.64)
Tolerant

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.
0.17Z-score
OE missense 0.96 (0.82–1.12)
113 obs / 118.2 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.0.20 (0.08–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.82–1.12)
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.1.09
0≤1.21.6
LoF obs/exp: 2 / 9.9Missense obs/exp: 113 / 118.2Syn Z: -0.48

ClinVar Variant Classifications

94 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic2
VUS38
Likely Benign11
Benign14
Conflicting2
27
Pathogenic
2
Likely Pathogenic
38
VUS
11
Likely Benign
14
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
24
0
27
Likely Pathogenic
0
0
2
0
2
VUS
0
33
5
0
38
Likely Benign
0
2
1
8
11
Benign
0
2
9
3
14
Conflicting
—2
Total040411194

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

View in ClinVar →

Protein Context — Lollipop Plot

EDN1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

EDN1-related auriculocondylar syndrome

strong
ARUndeterminedAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

EDN1-related question mark ears, isolated

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ENDOTHELIN 1; EDN1
MIM #131240 · *

Auriculocondylar syndrome 3

MIM #615706

Molecular basis of disorder known

Autosomal recessive

Question mark ears, isolated

MIM #612798

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.
Zhu MM et al.·JCI Insight
2024Functional
The extracellular matrix protein type I collagen and fibronectin are regulated by β-arrestin-1/endothelin axis in human ovarian fibroblasts.
Masi I et al.·J Exp Clin Cancer Res
2025
Biomimetic astrocyte cell membrane-fused nanovesicles for protecting neurovascular units in hypoxic ischemic encephalopathy.
Liu Z et al.·J Nanobiotechnology
2024
The EDN1 Missense Variant rs5370G > T Regulates Adaptation and Maladaptation under Hypobaric Hypoxia.
Palmo T et al.·Int J Environ Res Public Health
2022
Auriculocondylar syndrome: Pathogenesis, clinical manifestations and surgical therapies.
Li Q et al.·J Formos Med Assoc
2023Review
Clinical, Histologic, and Transcriptomic Evaluation of Sequential Fat Grafting for Morphea: A Nonrandomized Controlled Trial.
Liu J et al.·JAMA Dermatol
2024
Genomics of Fibromuscular Dysplasia.
Di Monaco S et al.·Int J Mol Sci
2018Review
Interleukin-30 subverts prostate cancer-endothelium crosstalk by fostering angiogenesis and activating immunoregulatory and oncogenic signaling pathways.
Ciummo SL et al.·J Exp Clin Cancer Res
2023
Fibromyalgia: A Review of Related Polymorphisms and Clinical Relevance.
Janssen LP et al.·An Acad Bras Cienc
2021Review
Endothelin in polycystic kidney disease.
Chang MY et al.·Contrib Nephrol
2011Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
tRF-31-PS5P4PW3FJHP inhibits hypoxia-induced proliferation of pulmonary artery endothelial cells by regulating EDN1 splicing via binding to LSM4.
Wang S et al.·Eur J Pharmacol
2026
Targeting IL6-Edn1-FoxO1 axis enables lung growth in mechanically ventilated newborn mice.
Hirani D et al.·Eur Respir J
2025🔓 Open Access
Study of the Association of EDN1 rs5370 Polymorphism to Type 2 Diabetes Complications.
Ahmed AM et al.·Int J Gen Med
2025🔓 Open Access
EWAS in COPD by biomass-burning smoke exposure identifies low levels of endothelin-1 by hypermethylation of EDN1.
García-Carmona S et al.·Epigenomics
2025🔓 Open Access
Crosstalk Between Gastric Cancer and Adjacent Mucosa Reveals EDN1-EDNRA-Mediated Regulation of Cancer Stemness and Immunomodulation Networks.
Zhu X et al.·J Cell Mol Med
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Fabry DiseaseEndothelial DysfunctionMicrovasculature

Characterizing the Retinal Microvasculature in Patients with Fabry Disease: a Prospective Observational Study

RECRUITING
NCT06758648Technical University of MunichStarted 2020-06-25
Dynamic retinal vessel analysis (DVA)Biochemistry and immune phenotypingQuestionnaires (Patient reported outcomes)
MigraineTranscranial Magnetic Stimulation Repetitive

Individualized Location-based rTMS for Migraine Treatment: A Multicenter Clinical Study

NOT YET RECRUITING
NCT07086274Phase NAFirst Affiliated Hospital of Zhejiang UniversityStarted 2025-07-25
Individualized location-based Repetitive Transcranial Magnetic StimulationTraditional location-based Repetitive Transcranial Magnetic Stimulation

External Resources

Links to major genomics databases and tools