EDN2

Chr 1

endothelin 2

Also known as: ET-2, ET2, PPET2

NCBI Gene: 1907 ENSG00000127129 UniProt: P20800

Endothelin-2 is a secreted vasoconstrictor peptide that binds to endothelin receptors and regulates vascular tone and various physiological processes including blood pressure control. Mutations in EDN2 cause Feingold syndrome type 2, an autosomal dominant developmental disorder characterized by microcephaly, limb malformations (particularly digital anomalies), and gastrointestinal atresias. The gene shows tolerance to loss-of-function variants, suggesting the pathogenic variants may act through alternative mechanisms.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the endothelin protein family of secretory vasoconstrictive peptides. The preproprotein is processed to a short mature form which functions as a ligand for the endothelin receptors that initiate intracellular signaling events. This gene product is involved in a wide range of biological processes, such as hypertension and ovulation. Altered expression of this gene is implicated in tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.02

Clinical Summary— EDN2

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Population Constraint (gnomAD)

Low constraint (pLI 0.06) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

25 VUS of 30 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.02LOEUF

pLI 0.060

Z-score 1.55

OE 0.39 (0.18–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.13Z-score

OE missense 0.97 (0.82–1.13)

108 obs / 111.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.18–1.02)

0≤0.351.4

Missense OE?0.97 (0.82–1.13)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 3 / 7.6Missense obs/exp: 108 / 111.8Syn Z: 0.79

This gene — mechanism propensity

0.6552th %ile

GOF

0.4972th %ile

LOF

0.4135th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

30 submitted variants in ClinVar

ClinVar

Classification Summary

VUS25

Likely Benign3

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	25	0	25
Likely Benign	3	0	3
Benign	0	1	1
Total	28	1	29

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap EDN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →