EDNRA

Chr 4AD

endothelin receptor type A

Also known as: ET-A, ETA, ETA-R, ETAR, ETRA, MFDA, hET-AR

NCBI Gene: 1909 ENSG00000151617 UniProt: P25101 OMIM: 131243

This gene encodes the receptor for endothelin-1, a peptide that plays a role in potent and long-lasting vasoconstriction. This receptor associates with guanine-nucleotide-binding (G) proteins, and this coupling activates a phosphatidylinositol-calcium second messenger system. Polymorphisms in this gene have been linked to migraine headache resistance. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

OMIM Research

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.252 OMIM phenotypes

Clinical Summary— EDNRA

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 71 VUS of 142 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.992

Z-score 3.79

OE 0.05 (0.02–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.80Z-score

OE missense 0.49 (0.42–0.57)

120 obs / 242.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.25)

0≤0.351.4

Missense OE?0.49 (0.42–0.57)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 1 / 18.7Missense obs/exp: 120 / 242.9Syn Z: 0.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEDNRA-related mandibulofacial dysostosis with alopeciaGOFAD

This gene — mechanism propensity

0.5772th %ile

GOF

0.6932th %ile

LOF

0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOFLOEUF 0.25

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.

Literature Evidence

GOFThe zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 25772936 ↗

ClinVar Variant Classifications

142 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS71

Likely Benign40

Benign21

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	2
Likely Pathogenic	0	0	0	0
VUS	69	1	1	71
Likely Benign	1	15	24	40
Benign	2	16	3	21
Total	74	32	28	134

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap EDNRA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →