EDN1

protein-coding

endothelin 1, the group of Endothelins

Gene summary

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]

MANE transcript

NM_001955.5

Inheritance

AR, AD

ClinVar variants

P:4U:34B:16

Top phenotype

Question-mark ears, isolated; Auriculocondylar Syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr6:12,290,361-12,297,194

External References & Databases

Ensembl (ENSG00000078401)

Transcript & Mutation Effects

hg38 • Region Span ~6.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

auriculocondylar syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0000107

Submitter: ClinGen

EDN1 was first reported in relation to autosomal recessive auriculocondylar syndrome 3 in 2013 (Gordon et al., PMID: 24268655). 3 missense variants that have been reported in 3 probands in 2 publications (PMIDs: 24268655, 35170830) are included in this curation. This gene-disease relationship is also supported by expression and protein interaction studies supporting a genetic interaction between EDN1 and PLCB3, and demonstrating expression of EDN1 in the arch epithelium, paraxial mesoderm-derived arch core, and arch vessel endothelium (PMIDs: 17239364, 9449664). Additionally, two mouse models indicate that mice deficient in the endothelin receptor ETA mimic human conditions including severe craniofacial malformations, and that mice deficient in EDN1 also demonstrate craniofacial anomalies (PMIDs: 9449664, 8152482). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date November 20, 2025 (SOP Version 11).

question mark ears, isolatedSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013013

Submitter: G2P

auriculocondylar syndrome 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014312

Submitter: PanelApp Australia

question mark ears, isolatedLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013013

Submitter: Labcorp Genetics (formerly Invitae)

auriculocondylar syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000107

Submitter: Orphanet

auriculocondylar syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014312

Submitter: Labcorp Genetics (formerly Invitae)

auriculocondylar syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014312

Submitter: G2P

Clinical Genomic Database (CGD)

Question-mark ears, isolated; Auriculocondylar Syndrome 3AD/AR

Manifestation: Craniofacial

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Conductive hearing loss has been described in one individual

Refs: 24268655

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EDN1 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 28

not providedTotal: 25

not specifiedTotal: 9

EDN1-related disorderTotal: 6

Question mark ears, isolatedTotal: 5

Auriculocondylar syndrome 3Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001955.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				8 clinvar	2 clinvar	10
missense	3 clinvar		34 clinvar	6 clinvar		43
nonsense	1 clinvar					1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	4	0	34	14	2	54

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001955.5	RefSeq	NP_001946.3	5	MANE Select
ENST00000379375.6	Ensembl	ENSP00000368683.5	5	MANE Select
NM_001168319.2	RefSeq	NP_001161791.1	5	Standard
NM_001416563.1	RefSeq	NP_001403492.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
edn1	Danio rerio	Structure: hyohyoideus Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

edn1

Danio rerio

Structure: hyohyoideus

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Relaxin signaling pathway - Homo sapiens (human)
AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)
TNF signaling pathway - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
prostaglandin biosynthetic process
branching involved in blood vessel morphogenesis
in utero embryonic development
histamine secretion

Molecular Function

cytokine activity
hormone activity
protein binding
endothelin A receptor binding
endothelin B receptor binding

Cellular Component

extracellular region
extracellular space
cytoplasm
transport vesicle
Weibel-Palade body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379375
Coding exons: 5
Length: 6832
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.169	113	118	0.956	0.00000660	1384
Missense (PolyPhen)		21	35.185	0.59685		427
Synonymous	-0.482	47	43.0	1.09	0.00000255	379
Loss of Function	2.33	2	9.91	0.202	4.19e-7	135

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Endothelins are endothelium-derived vasoconstrictor peptides.;
Disease: DISEASE: Auriculocondylar syndrome 3 (ARCND3) [MIM:615706]: A craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia. {ECO:0000269|PubMed:24268655}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.751

Intolerance Scores

LoFtool: 0.183
RVIS EVS: -0.21
RVIS percentile EVS: 38.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.521

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium