ENG

Chr 9

endoglin

Also known as: END, HHT1, ORW1

NCBI Gene: 2022 ENSG00000106991 UniProt: P17813

Endoglin is a homodimeric transmembrane glycoprotein of the vascular endothelium that functions as a TGF-beta coreceptor and regulates angiogenesis, vascular endothelial cell migration, and maintenance of normal adult vasculature structure and integrity. Mutations cause hereditary hemorrhagic telangiectasia type 1 (Osler-Rendu-Weber syndrome), a multisystemic vascular dysplasia with autosomal dominant inheritance. This condition primarily affects the vascular system with abnormal blood vessel formation leading to telangiectasias and arteriovenous malformations.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtTelangiectasia, hereditary hemorrhagic, 1

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

283

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

LOF

Mechanism· G2P

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GeneReview available — ENG

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 4.78

OE 0.09 (0.04–0.24)

Highly constrained

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

Missense Constraint?

0.93Z-score

OE missense 0.87 (0.79–0.95)

338 obs / 389.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.24)

0≤0.351.4

Missense OE?0.87 (0.79–0.95)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 3 / 32.3Missense obs/exp: 338 / 389.9Syn Z: -0.25

Background carrier burden — how many people carry a rare variant somewhere in ENG?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 67

816 rare PASS variants

Rare truncating (LoF)

1 in 8,000

50 rare PASS variants

Rare synonymous (reference)

1 in 79

378 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ENG. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 83	1 in 8,200
South Asian	~43k	1 in 61	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 67	1 in 1,000
European (Finnish)	~27k	1 in 170	1 in 4,100
Admixed American	~22k	1 in 65	≈ 1 in 9,200
African / African American	~21k	1 in 55	≈ 1 in 21,000
East Asian	~20k	1 in 75	≈ 1 in 9,700
Ashkenazi Jewish	~13k	1 in 160	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 83	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 15 coding exons well covered in gnomAD exomes. Genomes: 14 of 15 (exon 6 below).? see exons ↓