ENG

Summary

ENG (endoglin, HGNC:3349) is a protein-coding gene on chromosome 9q34.11, encoding Endoglin (P17813). Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 2022 — RefSeq curated summary.

At a glance

• Gene–disease (curated): telangiectasia, hereditary hemorrhagic, type 1 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 2,119 total — 489 pathogenic, 119 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 11 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 89
• Drug target: yes — 1 curated mechanism-of-action drug
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.37 (moderately constrained)
• MANE Select transcript: NM_001114753
• Interaction hub: 2,892 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3349
Approved symbol	ENG
Name	endoglin
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	END, HHT1, CD105
Ensembl gene	ENSG00000106991
Ensembl biotype	protein_coding
OMIM	131195
Entrez	2022

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 48 protein_coding, 14 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000373203

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 2, TSL 3: 1

ENST00000373203, ENST00000344849, ENST00000462196, ENST00000480266, ENST00000486329, ENST00000713956, ENST00000713957, ENST00000713995, ENST00000713996, ENST00000713997, ENST00000714046, ENST00000714047, ENST00000714076, ENST00000714077, ENST00000714078, ENST00000714079, ENST00000714080, ENST00000714081, ENST00000714082, ENST00000714083, ENST00000714084, ENST00000714102, ENST00000714103, ENST00000714126, ENST00000714127, ENST00000886302, ENST00000886303, ENST00000886304, ENST00000886305, ENST00000886306, ENST00000886307, ENST00000886308, ENST00000886309, ENST00000886310, ENST00000942917, ENST00000942918, ENST00000942919, ENST00000942920, ENST00000942921, ENST00000942922, ENST00000942923, ENST00000987120, ENST00000987123, ENST00001020278, ENST00001020279, ENST00001020282, ENST00001020283, ENST00001020284, ENST00001020286, ENST00001020290, ENST00001020292, ENST00001020293, ENST00001020295, ENST00001020296, ENST00001020297, ENST00001108795, ENST00001108796, ENST00001112487, ENST00001112488, ENST00001112489, ENST00001112490, ENST00001126442, ENST00001141124

RefSeq mRNA: 4 — MANE Select: NM_001114753 NM_000118, NM_001114753, NM_001278138, NM_001406715

CCDS: CCDS48029, CCDS6880, CCDS75906

Canonical transcript exons

ENST00000373203 — 15 exons

Exon	Start	End
ENSE00000729960	127818716	127818832
ENSE00000729963	127819622	127819660
ENSE00001181098	127815943	127816053
ENSE00001181101	127854289	127854658
ENSE00003297799	127829687	127829827
ENSE00003346729	127843094	127843245
ENSE00003438349	127825695	127825860
ENSE00003486427	127826510	127826672
ENSE00003605233	127819900	127820037
ENSE00003730037	127824304	127824446
ENSE00003736678	127818120	127818377
ENSE00003738385	127824800	127824974
ENSE00003742131	127817149	127817203
ENSE00004022109	127825231	127825357
ENSE00004022732	127815016	127815806

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 99.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.3270 / max 1114.6175, expressed in 1387 samples.

Highest expression (Bgee): lung, atrium auricular region, cardiac atrium, apex of heart, lobe of thyroid gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ENG is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

13 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	sqtl	3.8e-67	+0.93	9:127842834:C:CA
Whole Blood	eqtl	9.7e-06	-0.17	9:127842834:C:CA
Cells Cultured fibroblasts	eqtl	5.7e-05	+0.08	9:127838998:C:T
Thyroid	eqtl	9.0e-05	+0.17	9:127838998:C:T
Artery Tibial	eqtl	1.2e-03	+0.10	9:127838998:C:T
Testis	eqtl	1.2e-03	-0.65	9:128420732:G:A
Artery Aorta	eqtl	1.1e-02	-0.52	9:128746704:C:A
Artery Coronary	eqtl	1.2e-02	-0.61	9:127843069:C:A
Nerve Tibial	eqtl	1.3e-02	+0.24	9:128151359:A:T
Lung	eqtl	1.9e-02	+0.59	9:128313876:C:T
Whole Blood	sqtl	2.4e-02	-1.08	9:128098558:G:T
Esophagus Muscularis	eqtl	3.3e-02	-0.48	9:127271162:C:T
Brain Cortex	eqtl	4.5e-02	-0.34	9:127760437:G:A

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
102598	29.4691	1210
102600	18.3331	1312
102599	14.4962	1211
102595	2.6488	729
102597	1.9820	487
102601	0.6847	365
102596	0.5039	264
102594	0.2092	75

Top tissues by expression

showing 100 of 290 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.49	gold quality
right atrium auricular region	UBERON:0006631	99.35	gold quality
cardiac atrium	UBERON:0002081	99.23	gold quality
apex of heart	UBERON:0002098	99.22	gold quality
right lobe of thyroid gland	UBERON:0001119	99.10	gold quality
left ovary	UBERON:0002119	99.05	gold quality
metanephros cortex	UBERON:0010533	99.02	gold quality
right ovary	UBERON:0002118	99.00	gold quality
right coronary artery	UBERON:0001625	98.97	gold quality
upper lobe of left lung	UBERON:0008952	98.92	gold quality
ascending aorta	UBERON:0001496	98.90	gold quality
thoracic aorta	UBERON:0001515	98.89	gold quality
descending thoracic aorta	UBERON:0002345	98.84	gold quality
left coronary artery	UBERON:0001626	98.75	gold quality
upper lobe of lung	UBERON:0008948	98.72	gold quality
coronary artery	UBERON:0001621	98.69	gold quality
omental fat pad	UBERON:0010414	98.69	gold quality
peritoneum	UBERON:0002358	98.64	gold quality
left lobe of thyroid gland	UBERON:0001120	98.61	gold quality
left uterine tube	UBERON:0001303	98.50	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.42	gold quality
spleen	UBERON:0002106	98.34	gold quality
heart left ventricle	UBERON:0002084	98.20	gold quality
endocervix	UBERON:0000458	98.09	gold quality
cardiac ventricle	UBERON:0002082	98.09	gold quality
body of uterus	UBERON:0009853	97.98	gold quality
right uterine tube	UBERON:0001302	97.97	gold quality
thyroid gland	UBERON:0002046	97.85	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.85	gold quality
heart	UBERON:0000948	97.77	gold quality
tibial nerve	UBERON:0001323	97.57	gold quality
aorta	UBERON:0000947	97.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.30	gold quality
stromal cell of endometrium	CL:0002255	97.20	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.91	gold quality
right adrenal gland	UBERON:0001233	96.89	gold quality
ectocervix	UBERON:0012249	96.88	gold quality
lower esophagus	UBERON:0013473	96.84	gold quality
left adrenal gland	UBERON:0001234	96.83	gold quality
pericardium	UBERON:0002407	96.81	gold quality
left testis	UBERON:0004533	96.79	gold quality
mucosa of stomach	UBERON:0001199	96.72	gold quality
left adrenal gland cortex	UBERON:0035825	96.72	gold quality
adipose tissue	UBERON:0001013	96.67	gold quality
lower lobe of lung	UBERON:0008949	96.58	gold quality
tendon of biceps brachii	UBERON:0008188	96.53	gold quality
adrenal cortex	UBERON:0001235	96.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.49	gold quality
gall bladder	UBERON:0002110	96.43	gold quality
right adrenal gland cortex	UBERON:0035827	96.35	gold quality
right testis	UBERON:0004534	96.32	gold quality
olfactory bulb	UBERON:0002264	96.30	gold quality
smooth muscle tissue	UBERON:0001135	96.28	gold quality
popliteal artery	UBERON:0002250	96.15	gold quality
connective tissue	UBERON:0002384	96.14	gold quality
tibial artery	UBERON:0007610	96.14	gold quality
adenohypophysis	UBERON:0002196	95.96	gold quality
myometrium	UBERON:0001296	95.95	gold quality
myocardium	UBERON:0002349	95.82	gold quality
lung	UBERON:0002048	95.72	gold quality
vena cava	UBERON:0004087	95.70	gold quality
testis	UBERON:0000473	95.61	gold quality
adrenal gland	UBERON:0002369	95.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.41	gold quality
caecum	UBERON:0001153	95.25	gold quality
vermiform appendix	UBERON:0001154	95.22	gold quality
renal medulla	UBERON:0000362	95.18	gold quality
adult mammalian kidney	UBERON:0000082	95.17	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.09	gold quality
fundus of stomach	UBERON:0001160	94.97	gold quality
lymph node	UBERON:0000029	94.81	gold quality
placenta	UBERON:0001987	94.74	gold quality
ovary	UBERON:0000992	94.69	gold quality
body of stomach	UBERON:0001161	94.62	gold quality
gastrocnemius	UBERON:0001388	94.51	gold quality
layer of synovial tissue	UBERON:0007616	94.32	gold quality
decidua	UBERON:0002450	94.25	gold quality
small intestine	UBERON:0002108	94.04	gold quality
muscle of leg	UBERON:0001383	93.92	gold quality
minor salivary gland	UBERON:0001830	93.84	gold quality
left ventricle myocardium	UBERON:0006566	93.79	gold quality
body of pancreas	UBERON:0001150	93.68	gold quality
type B pancreatic cell	CL:0000169	93.60	gold quality
vagina	UBERON:0000996	93.60	gold quality
esophagus	UBERON:0001043	93.58	gold quality
transverse colon	UBERON:0001157	93.54	gold quality
prostate gland	UBERON:0002367	93.52	gold quality
pituitary gland	UBERON:0000007	93.49	gold quality
right lobe of liver	UBERON:0001114	93.41	gold quality
skin of leg	UBERON:0001511	93.30	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.22	gold quality
heart right ventricle	UBERON:0002080	92.91	gold quality
urethra	UBERON:0000057	92.82	gold quality
stomach	UBERON:0000945	92.70	gold quality
synovial joint	UBERON:0002217	92.68	gold quality
saphenous vein	UBERON:0007318	92.66	gold quality
cardia of stomach	UBERON:0001162	92.53	gold quality
skin of abdomen	UBERON:0001416	92.43	gold quality
colonic epithelium	UBERON:0000397	92.40	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 23.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	2466.23
E-GEOD-135922	yes	2231.89
E-MTAB-8142	yes	1832.49
E-MTAB-6678	yes	1584.50
E-HCAD-11	yes	1195.16
E-HCAD-9	yes	903.23
E-MTAB-10287	yes	654.45
E-GEOD-100618	yes	213.94
E-MTAB-6701	yes	74.34
E-HCAD-10	yes	62.45
E-MTAB-10553	yes	60.74
E-HCAD-1	yes	50.39
E-MTAB-8410	yes	38.31
E-CURD-46	yes	34.54
E-CURD-119	yes	27.95

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Heart muscle	tissue	179.2	not detected
Spleen	tissue	118.3	not detected
Ovary	tissue	116.0	not detected
Adipose tissue	tissue	107.4	not detected
Lung	tissue	100.3	not detected
Vagina	tissue	92.6	not detected
Placenta	tissue	88.1	medium
Appendix	tissue	75.7	not detected
Seminal vesicle	tissue	69.2	not detected
Choroid plexus	tissue	67.6
Smooth muscle	tissue	61.4	not detected
Pituitary gland	tissue	57.1
Urinary bladder	tissue	56.1	not detected
Gallbladder	tissue	55.0	not detected
Skeletal muscle	tissue	51.1	not detected
Tongue	tissue	51.1
Testis	tissue	49.8	medium
Kidney	tissue	49.1	medium
Liver	tissue	47.3	not detected
Endometrium 1	tissue	46.9	not detected
Fallopian tube	tissue	40.8	not detected
Lymph node	tissue	40.7	not detected
Thyroid gland	tissue	38.9	not detected
Adrenal gland	tissue	38.4	not detected
Locus coeruleus	tissue	36.8
Hippocampus	tissue	36.3	not detected
Cervix	tissue	33.6	not detected
Epididymis	tissue	33.1	not detected
Duodenum	tissue	31.2	not detected
Parathyroid gland	tissue	27.9	not detected
Salivary gland	tissue	26.7	not detected
Pancreas	tissue	26.5	not detected
Nucleus accumbens	tissue	25.7
Small intestine	tissue	25.0	not detected
Skin 1	tissue	23.7	not detected
Postcentral gyrus	tissue	22.6
Prostate	tissue	22.5	not detected
Colon	tissue	21.5	not detected
Superior colliculi	tissue	21.5
Caudate putamen	tissue	19.8
Stomach 1	tissue	19.7	not detected
Esophagus	tissue	19.7	not detected
Thalamus	tissue	19.6
Substantia nigra	tissue	19.1
Putamen	tissue	18.1
Pons	tissue	17.7
Bone marrow	tissue	17.7	not detected
Frontal cortex	tissue	17.6
Tonsil	tissue	16.6	not detected
Rectum	tissue	16.5	not detected
Midbrain	tissue	16.3
Medulla oblongata	tissue	16.3
Thymus	tissue	16.1
Cerebral cortex	tissue	15.8	low
Insular cortex	tissue	15.8
Spinal cord	tissue	15.5
Motor cortex	tissue	15.3
Somatosensory cortex	tissue	14.6
Occipital cortex	tissue	14.6
Prefrontal cortex	tissue	14.4

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (348.8), Anterior thalamic nucleus, ventral (90.2), Posterior thalamic nucleus (72.9), Dorsal cochlear nucleus (72.6), Reticulotegmental nucleus (67.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets:

Target	Regulation
BMP2	Activation
CD34	Repression
SNAI1	Activation

Upstream regulators (CollecTRI, top): ACVRL1, EGR1, ELF1, ERG, GDF2, HIF1A, KLF4, KLF6, NR1H3, SP1, SSRP1, TGFB1

miRNA regulators (miRDB)

Targeting ENG by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 45 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-3920	97.75	69.02	1168

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.374, missense Z 1.28 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000373203 — one region, missense o/e 0.86. ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• mutational analysis and genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community (Akita prefecture) in northern Japan (PMID:11793473)
• CLL B cells consistently express endoglin mRNA; co-expression of angiogenic molecules and receptors suggest autocrine pathways of stimulation. (PMID:11986954)
• expression marks principally small, probably newly formed tumor vessels in the prostate and is a promising prognostic marker for prostate cancer (PMID:11987155)
• endoglin expression on dermal endothelial cells was significantly enhanced in scleroderma but levels on circulating monocytes and in the serum were within normal limits (PMID:12009077)
• Extracellular and cytoplasmic domains of endoglin interact with tgf-beta I and II receptors (PMID:12015308)
• basal endoglin transcription (highly dependent on Sp1) may switch from a constitutive to an inducible state through Sp1 interaction with HIF-1 and Smad transcription factors, induced by hypoxia and TGF-beta, respectively (PMID:12228247)
• Inducible expression of human endoglin during inflammation and wound healing in vivo. Changes in endoglin expression from the normal quiescent state through the inflammatory changes and angiogenesis during dermal wound healing. (PMID:12365720)
• identified as a regulator of cell adhesion, motility and invasion in human prostate; loss of endoglin expression appears to be associated with prostate cancer progression, at least in vitro (PMID:12447690)
• endoglin and betaglycan have a critical role in the regulation of TGFbeta signaling in chondrocytes (PMID:12568406)
• No association was found between the 6bINS polymorphism or 4 SNPs in endoglin (ENG) and intracranial aneurysm (IA) and no linkage between the ENG locus and IA, indicating ENG is not a major susceptibility gene for IA in a Japanese population (PMID:12775886)
• Tumour microvessel density quantified using a Mab to CD105 is an independent prognostic parameter for survival of patients with colorectal cancer (PMID:12778073)
• study showed that endoglin, by staining the proliferating microvessels in endometrial carcinoma, is a more specific and sensitive marker for tumor angiogenesis than is the commonly used pan-endothelial marker, CD31 antigen (PMID:12819391)
• Up-regulation of CD105 in synovial cells of rheumatoid arthritis & psoriatic lesions implies a possible role in their pathogenesis. CD105 gene expression in endothelial cells is downregulated by the TNF alpha & downregulated by TGF beta 1. (PMID:12820370)
• A questionnaire based study provides evidence that the hereditary hemorrhagic telangietasia (HHT) phenotype caused by mutations in endoglin (HHT1) is distinct from, and more severe than, HHT caused by mutations in ALK1 (HHT2). (PMID:12920067)
• cell membrane glycoprotein expressed on endothelial cells and on tumor-associated vascular endothelium; accessory component of the transforming growth factor -beta receptor complex and is involved in vascular development and remodelling (review) (PMID:14528280)
• CD105, as a receptor of TGF-beta1, can regulate the biological effect of TGF-beta1 in tumor angiogenesis. (PMID:14669355)
• It is concluded that CD105 immunoexpression in breast carcinomas is an independent prognostic indicator in node-negative patients, better in terms of overall survival than Tie-2/Tek and CD31 (PMID:14991534)
• Inverse regulation in the expression of endoglin and lumican. (PMID:14996436)
• Mutational analysis of the ENG gene in hereditary hemorrhagic telangiectasia patients. (PMID:15024723)
• Increased CD105 expression is associated with high risk for metastasis of breast carcinomas (PMID:15067342)
• Endoglin interacts with LIM domain-containing proteins, and associated adapter proteins, affecting sites of focal adhesion. (PMID:15084601)
• Endoglin-dependent inhibition of cell migration, reduction of focal adhesion-associated p130(cas)/CrkII protein levels, tyrosine phosphorylation of p130(cas), and focal adhesion-associated endoglin levels are mediated by the cytosolic domain. (PMID:15084601)
• Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins (PMID:15148318)
• CD105-determined microvascular density correlates with the degree of fibrosis and is prognostically relevant and findings provide a rationale for the investigational use of anti-CD105-targeted drugs in chronic idiopathic myelofibrosis (CIMF). (PMID:15272276)
• VEGF mRNA expression levels seem to be directly associated with VEGF functions at the protein levelin breast cancer, whereas this seems not to be the case for CD105 (endoglin) mRNA levels. (PMID:15274325)
• Endoglin expression negatively regulates basal and TGF-beta1-induced CTGF and collagen expression and synthesis. (PMID:15319534)
• Mutation found in 53% of hereditary hemorragic telangiectasia patients. (PMID:15517393)
• thrombin via PAR1 induced the internalization of endoglin and type-II TGF-beta receptor (TbetaRII) but not type-I receptors in human ECs (PMID:15522964)
• The CD105 expression, as a marker of angiogenesis, was evaluated in myomas obtained after surgery. (PMID:15631865)
• CD105 staining of the microvessels in the adjacent non-tumorous liver tissues is predictive of early recurrence. (PMID:15633211)
• A branch-site mutation leading to abnormal splicing of exon 13 of the endoglin transcript was identified in a child with hereditary hemorrhagic telangiectasia related pulmonary arterial hypertension. (PMID:15687131)
• Extracellular and cytoplasmic domains of the auxiliary TGF-beta receptor endoglin interact with ALK-1 (a type I TGF-beta receptor). Endoglin potentiates TGF-beta/ALK1 signaling. (PMID:15702480)
• A new mutation, c.1844C>T, was found in an Osler-Rendu-Weber patient. (PMID:15712270)
• 6 new mutations were found: 2 nonsense mutations in exons 6 and 8, deletions in exons 5 and 11, and splice site mutations in exon 12 and intron 8. (PMID:15712271)
• Eng is an essential component of the eNOS activation pathway, where it promotes coupling of eNOS activity by facilitating its association with Hsp90. (PMID:15718503)
• endoglin is differentially expressed in human carcinoma and sarcoma cells and its overexpression modulates the proliferative rate of human solid tumour cells (PMID:15809709)
• data show that the expression of endoglin and S100A13 protein corresponds to the activation of the endothelial cells in the process of endometriotic angiogenesis (PMID:15821778)
• These results demonstrate the importance of ACVRL1 and ENG mutations in German hereditary hemorrhagic telangiectasia (HHT) patients displaying mutation frequencies over 80%. (PMID:15880681)
• This comparison of neo-angiogenesis performed by analysing CD105 expression seems to suggest that the biological behaviour of head and neck BSCCs is similar to that of site- and stage-matched conventional SCCs (PMID:15966703)
• endoglin is not associated with intracranial aneurysms (PMID:15976502)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000107130
mus_musculus	Eng	ENSMUSG00000026814
rattus_norvegicus	Eng	ENSRNOG00000050190

Paralogs (2): TGFBR3 (ENSG00000069702), TGFBR3L (ENSG00000260001)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95392) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 65 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal vitelline vasculature morphology	5
abnormal blood vessel morphology	3
embryonic growth retardation	3
abnormal vascular smooth muscle morphology	3
embryonic lethality during organogenesis, complete penetrance	3
abnormal heart development	2
decreased embryo size	2
hemorrhage	2
premature death	2
abnormal pharyngeal arch morphology	2
abnormal dorsal aorta morphology	2
abnormal vascular wound healing	2
pericardial effusion	2
arteriovenous malformation	2
increased neutrophil cell number	1
abnormal vascular development	1
blood vessel atresia	1
abnormal heart morphology	1
abnormal heart looping	1
enlarged heart	1
ruffled hair	1
microcephaly	1
weight loss	1
decreased locomotor activity	1
dehydration	1

+40 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Sus scrofa	P35054	84.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ST6GALNAC4-ST6GALNAC6-AK1	ncRNA	123987602
AK1	protein-coding	203
ST6GALNAC4	protein-coding	27090
ST6GALNAC6	protein-coding	30815
MIR4672	ncRNA	100616429
MIR2861	ncRNA	100422910
SH2D3C	protein-coding	10044
MIR3960	ncRNA	100616250
FPGS	protein-coding	2356
CDK9	protein-coding	1025
TTC16	protein-coding	158248
TOR2A	protein-coding	27433
PIP5KL1	protein-coding	138429
DPM2	protein-coding	8818

Protein

Protein identifiers

Endoglin — P17813 (reviewed: P17813)

All UniProt accessions (20): A0AAQ5BH38, A0AAQ5BHA3, A0AAQ5BHA9, A0AAQ5BHC0, A0AAQ5BHC4, A0AAQ5BHE8, A0AAQ5BHF3, A0AAQ5BHF5, A0AAQ5BHF7, A0AAQ5BHG1, A0AAQ5BHG4, A0AAQ5BHG5, A0AAQ5BHG8, A0AAQ5BHH6, A0AAQ5BHI3, A0AAQ5BHI8, A0AAQ5BHM6, P17813, F5GX88, Q5T9B9

UniProt curated annotations — full annotation on UniProt →

Function. Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis. Required for normal structure and integrity of adult vasculature. Regulates the migration of vascular endothelial cells. Required for normal extraembryonic angiogenesis and for embryonic heart development. May regulate endothelial cell shape changes in response to blood flow, which drive vascular remodeling and establishment of normal vascular morphology during angiogenesis. May play a critical role in the binding of endothelial cells to integrins and/or other RGD receptors. Acts as a TGF-beta coreceptor and is involved in the TGF-beta/BMP signaling cascade that ultimately leads to the activation of SMAD transcription factors. Required for GDF2/BMP9 signaling through SMAD1 in endothelial cells and modulates TGFB1 signaling through SMAD3.

Subunit / interactions. Homodimer; disulfide-linked. Forms a heteromeric complex with the signaling receptors for transforming growth factor-beta: TGFBR1 and/or TGFBR2. It is able to bind TGFB1 and TGFB2 with high affinity, but not TGFB3. Interacts with GDF2, forming a heterotetramer with a 2:2 stoichiometry. Interacts with ACVRL1. Can form a heteromeric complex with GDF2 and ACVRL1. Interacts with BMP10. Interacts with DYNLT4. Interacts with ARRB2.

Subcellular location. Cell membrane.

Tissue specificity. Detected on umbilical veil endothelial cells. Detected in placenta (at protein level). Detected on endothelial cells.

Disease relevance. Telangiectasia, hereditary hemorrhagic, 1 (HHT1) [MIM:187300] A multisystemic vascular dysplasia leading to dilation of permanent blood vessels and arteriovenous malformations of skin, mucosa, and viscera. The disease is characterized by recurrent epistaxis and gastro-intestinal hemorrhage. Visceral involvement includes arteriovenous malformations of the lung, liver, and brain. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ZP domain mediates dimerization. The N-terminal OR region is composed of two intertwined domains (OR1 and OR2) with a common, novel fold. Each contains 12 beta-strands that form a parallel beta-helix-like structure, plus a single alpha-helix. The OR1 region mediates interaction with GDF2.

Isoforms (2)

UniProt ID	Names	Canonical?
P17813-1	Long	yes
P17813-2	Short

RefSeq proteins (4): NP_000109, NP_001108225, NP_001265067, NP_001393644 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR058899	TGFBR3/Endoglin-like_N	Domain

Pfam: PF26060

UniProt features (141 total): sequence variant 49, strand 36, mutagenesis site 11, helix 8, disulfide bond 8, region of interest 6, glycosylation site 5, turn 4, compositionally biased region 2, modified residue 2, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, short sequence motif 1, transmembrane region 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
5I04	Crystal structure of the orphan region of human endoglin/CD105	X-RAY DIFFRACTION	2.42
5HZV	Crystal structure of the zona pellucida module of human endoglin/CD105	X-RAY DIFFRACTION	2.7
5HZW	Crystal structure of the orphan region of human endoglin/CD105 in complex with BMP9	X-RAY DIFFRACTION	4.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17813-F1	80.84	0.40

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Candidate cardiovascular disease genes, Disease related genes, Human disease related genes, Congenital malformations, Congenital malformations of the circulatory system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2)

Type	Positions
Phosphoserine	646, 649

Disulfide bonds (8)

Type	Positions
Disulfide bond	30–207, 53–182, 242–330, 350–382, 363–442, 394–412, 493–549
Interchain	516

Glycosylation sites (5)

Type	Positions
N-linked (glcnac…) asparagine	88, 102, 121, 134, 307

Mutagenesis-validated functional residues (11)

Position	Phenotype
246	no effect on interaction with gdf2.
269	impairs protein folding, but does not abolish interaction with gdf2.
270–271	loss of interaction with gdf2.
277	no effect on interaction with gdf2.
278	loss of interaction with gdf2.
282	loss of interaction with gdf2.
290	no effect on interaction with gdf2.
350	impairs protein folding. impairs protein folding; when associated with c-382.
382	impairs protein folding. impairs protein folding; when associated with c-350.
516	loss of dimerization via zp domain.
650	loss of interaction with arrb2.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 618 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MODULE_52, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS

GO Biological Process (46): negative regulation of transcription by RNA polymerase II (GO:0000122), branching involved in blood vessel morphogenesis (GO:0001569), vasculogenesis (GO:0001570), response to hypoxia (GO:0001666), negative regulation of endothelial cell proliferation (GO:0001937), heart looping (GO:0001947), positive regulation of systemic arterial blood pressure (GO:0003084), outflow tract septum morphogenesis (GO:0003148), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), endocardial cushion morphogenesis (GO:0003203), cardiac ventricle morphogenesis (GO:0003208), cardiac atrium morphogenesis (GO:0003209), ventricular trabecula myocardium morphogenesis (GO:0003222), regulation of DNA-templated transcription (GO:0006355), cell adhesion (GO:0007155), transforming growth factor beta receptor signaling pathway (GO:0007179), negative regulation of gene expression (GO:0010629), cell migration (GO:0016477), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), central nervous system vasculogenesis (GO:0022009), extracellular matrix disassembly (GO:0022617), regulation of cell adhesion (GO:0030155), negative regulation of cell migration (GO:0030336), BMP signaling pathway (GO:0030509), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), positive regulation of BMP signaling pathway (GO:0030513), dorsal aorta morphogenesis (GO:0035912), wound healing (GO:0042060), regulation of cell population proliferation (GO:0042127), positive regulation of transcription by RNA polymerase II (GO:0045944), smooth muscle tissue development (GO:0048745), artery morphogenesis (GO:0048844), venous blood vessel morphogenesis (GO:0048845), cell motility (GO:0048870), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), atrial cardiac muscle tissue morphogenesis (GO:0055009), cell chemotaxis (GO:0060326), positive regulation of SMAD protein signal transduction (GO:0060391), negative regulation of SMAD protein signal transduction (GO:0060392), detection of hypoxia (GO:0070483), vascular associated smooth muscle cell development (GO:0097084), positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation (GO:1905007), positive regulation of vascular associated smooth muscle cell differentiation (GO:1905065), atrioventricular canal morphogenesis (GO:1905222), angiogenesis (GO:0001525), regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090092)

GO Molecular Function (13): transmembrane signaling receptor activity (GO:0004888), type II transforming growth factor beta receptor binding (GO:0005114), galactose binding (GO:0005534), glycosaminoglycan binding (GO:0005539), coreceptor activity (GO:0015026), signaling receptor activator activity (GO:0030546), type I transforming growth factor beta receptor binding (GO:0034713), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), activin binding (GO:0048185), transforming growth factor beta binding (GO:0050431), protein binding (GO:0005515), BMP binding (GO:0036122)

GO Cellular Component (6): plasma membrane (GO:0005886), focal adhesion (GO:0005925), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), signaling receptor complex (GO:0043235), endothelial microparticle (GO:0072563)

GO top-level categories

showing 60 of 63 GO namespaces:

Category	Terms
signaling receptor activity	3
blood vessel morphogenesis	2
cardiac chamber morphogenesis	2
regulation of gene expression	2
transforming growth factor beta receptor binding	2
cytokine binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
angiogenesis	1
branching morphogenesis of an epithelial tube	1
cell differentiation	1
response to stress	1
response to decreased oxygen levels	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
regulation of systemic arterial blood pressure	1
positive regulation of blood pressure	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
endocardial cushion formation	1
cardiac epithelial to mesenchymal transition	1
heart morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1
cardiac ventricle development	1
cardiac atrium development	1
ventricular cardiac muscle tissue morphogenesis	1
heart trabecula morphogenesis	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
cellular process	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
cell motility	1
transforming growth factor beta receptor signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to transforming growth factor beta stimulus	1
vasculogenesis	1
monosaccharide binding	1
carbohydrate derivative binding	1
signaling receptor regulator activity	1
molecular function activator activity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
protein-containing complex binding	1
growth factor binding	1
binding	1
membrane	1
cell periphery	1
cell-substrate junction	1
plasma membrane	1
cell surface	1
side of membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 35 of 66 annotations. The rest are phylogenetic / computational / electronic (IEA).

35 experimentally-supported GO terms:

GO term	NS	Evidence
cell chemotaxis	BP	mutant phenotype
cell migration	BP	mutant phenotype
cell motility	BP	mutant phenotype
central nervous system vasculogenesis	BP	mutant phenotype
detection of hypoxia	BP	direct assay
extracellular matrix disassembly	BP	mutant phenotype
negative regulation of SMAD protein signal transduction	BP	mutant phenotype
negative regulation of cell migration	BP	direct assay
negative regulation of endothelial cell proliferation	BP	mutant phenotype
negative regulation of transcription by RNA polymerase II	BP	direct assay
positive regulation of BMP signaling pathway	BP	direct assay
positive regulation of SMAD protein signal transduction	BP	direct assay
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	BP	genetic interaction
positive regulation of systemic arterial blood pressure	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	direct assay
regulation of DNA-templated transcription	BP	mutant phenotype
regulation of transforming growth factor beta receptor signaling pathway	BP	direct assay
response to hypoxia	BP	direct assay
transforming growth factor beta receptor signaling pathway	BP	direct assay
vasculogenesis	BP	mutant phenotype
wound healing	BP	mutant phenotype
cell surface	CC	direct assay
external side of plasma membrane	CC	direct assay
focal adhesion	CC	high-throughput assay
plasma membrane	CC	direct assay
signaling receptor complex	CC	physical interaction
coreceptor activity	MF	direct assay
galactose binding	MF	direct assay
glycosaminoglycan binding	MF	direct assay
identical protein binding	MF	physical interaction
protein homodimerization activity	MF	physical interaction
signaling receptor activator activity	MF	direct assay
transforming growth factor beta binding	MF	physical interaction
type I transforming growth factor beta receptor binding	MF	physical interaction
type II transforming growth factor beta receptor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,892 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENG	ACVRL1	P37023	984
ENG	THY1	P04216	935
ENG	NT5E	P21589	930
ENG	CD34	P28906	918
ENG	CD44	P16070	886
ENG	ITGB1	P05556	885
ENG	PTPRC	P08575	884
ENG	PECAM1	P16284	883
ENG	ALCAM	Q13740	880
ENG	TGFB1	P01137	866
ENG	BMPR2	Q13873	849
ENG	CD19	P15391	822
ENG	MCAM	P43121	800
ENG	GDF2	Q9UK05	795
ENG	ITGAM	P11215	774

IntAct

Human interaction partners of ENG in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 31 partners by confidence:

Partner	Interaction type	MIscore	Records
GDF2	direct interaction	0.660	9
LGALS3	direct interaction	0.630	5
TRIM21	physical association	0.610	6
ITGA5	physical association	0.560	4
ITGB1	physical association	0.520	3
TGFB1	direct interaction	0.440	2
ABCF1	direct interaction	0.440	1
ABLIM1	direct interaction	0.440	1
CAPRIN1	direct interaction	0.440	1
CTTN	direct interaction	0.440	1
CWC15	direct interaction	0.440	1
HIRIP3	direct interaction	0.440	1
HYCC2	direct interaction	0.440	1
KCNAB1	direct interaction	0.440	1
LMNA	direct interaction	0.440	1
NSRP1	direct interaction	0.440	1
ORC6	direct interaction	0.440	1
PRRC2B	direct interaction	0.440	1
RAD51AP1	direct interaction	0.440	1
RTF1	direct interaction	0.440	1
SAFB2	direct interaction	0.440	1
SCEL	direct interaction	0.440	1
SH3RF2	direct interaction	0.440	1
SMAP1	direct interaction	0.440	1
WASH2P	direct interaction	0.440	1
YTHDF2	direct interaction	0.440	1
ARRB2	physical association	0.400	1
LRG1	physical association	0.400	1
ACVRL1	association	0.350	1
IGKV2-28	association	0.350	1

BioGRID (229 interactions; top human partners by supporting records): TGFBR1 (Affinity Capture-Western; 7 records), TGFBR2 (Affinity Capture-Western; 6 records), LGALS3 (Affinity Capture-Western; 4 records), TRIM21 (Affinity Capture-Western; 4 records), ACVR2A (Affinity Capture-Western; 2 records), ACVRL1 (Affinity Capture-Western; 2 records), ABHD14B (Affinity Capture-MS), ABI3 (Affinity Capture-MS), ACIN1 (Affinity Capture-MS), ACVR1 (Affinity Capture-Western), ACVR2B (Affinity Capture-Western), AEN (Affinity Capture-MS), ARAF (Affinity Capture-MS), ARF4 (Affinity Capture-MS), ARL6IP1 (Affinity Capture-MS)

SIGNOR signaling

showing 6 of 7 signaling interactions:

A	Effect	B	Mechanism
ERG	“up-regulates quantity by expression”	ENG	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	ENG	“transcriptional regulation”
TGFB1	“up-regulates quantity by expression”	ENG	“transcriptional regulation”
SRC	“down-regulates quantity by destabilization”	ENG	phosphorylation
ENG	“up-regulates activity”	GDF2	binding
ENG	“up-regulates activity”	BMP10	binding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
Endoglin homodimer	1	ENG

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by TGFB family members	5	28.8×	1e-04
Cellular responses to stimuli	5	7.9×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
angiogenesis	5	10.8×	4e-03
positive regulation of cell migration	5	10.6×	4e-03

Disease & clinical

Genetic variants

Variant evidence for ENG: 2,119 ClinVar records (608 pathogenic / likely pathogenic); 29 ClinGen expert-panel interpretations; 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

2,119 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	489
Likely pathogenic	119
Uncertain significance	570
Likely benign	632
Benign	34

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 608 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
407115	NM_001114753.3(ENG):c.991G>A (p.Gly331Ser)	Pathogenic	reviewed by expert panel	13
213212	NM_001114753.3(ENG):c.1586G>A (p.Arg529His)	Pathogenic	reviewed by expert panel	11
237027	NM_001114753.3(ENG):c.447G>C (p.Trp149Cys)	Pathogenic	reviewed by expert panel	11
430375	NM_001114753.3(ENG):c.1145G>A (p.Cys382Tyr)	Pathogenic	reviewed by expert panel	4
458346	NM_001114753.3(ENG):c.2T>G (p.Met1Arg)	Pathogenic	reviewed by expert panel	3
618625	NM_001114753.3(ENG):c.1701del (p.Val568fs)	Pathogenic	reviewed by expert panel	2
435060	NM_001114753.3(ENG):c.662T>C (p.Leu221Pro)	Likely pathogenic	reviewed by expert panel	8
982495	NM_001114753.3(ENG):c.1268A>G (p.Asn423Ser)	Likely pathogenic	reviewed by expert panel	7
528065	NM_001114753.3(ENG):c.1319T>G (p.Val440Gly)	Likely pathogenic	reviewed by expert panel	6
995600	NM_001114753.3(ENG):c.1807G>A (p.Gly603Arg)	Likely pathogenic	reviewed by expert panel	5
995686	NM_001114753.3(ENG):c.1645T>G (p.Cys549Gly)	Likely pathogenic	reviewed by expert panel	4
1466744	NM_001114753.3(ENG):c.1517T>A (p.Leu506His)	Likely pathogenic	reviewed by expert panel	4
265371	NM_001114753.3(ENG):c.277C>T (p.Arg93Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	12
439644	NM_001114753.3(ENG):c.511C>T (p.Arg171Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	12
265370	NM_001114753.3(ENG):c.360+1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	11

Per-variant reference — Sugi Variant

Explore ENG’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

ClinGen expert-panel interpretations (29)

Expert ACMG interpretations from Hereditary Hemorrhagic Telangiectasia VCEP for telangiectasia, hereditary hemorrhagic, type 1 — a higher-authority tier than individual ClinVar submissions.

Assertion	Variants
Pathogenic	6
Likely Pathogenic	6
Uncertain Significance	7
Likely Benign	8
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 46 predictions of 1,248):

Position(s)	Effect	Δscore	Sites
9:127815807–127815808	acceptor_loss	1.0000	6
9:127815941–127815942	donor_loss	1.0000	3
9:127816054–127816055	acceptor_loss	1.0000	3
9:127817147–127817148	donor_loss	1.0000	5
9:127817204–127817205	acceptor_loss	1.0000	5
9:127818833–127818834	acceptor_loss	1.0000	6
9:127824798–127824799	donor_loss	1.0000	5
9:127824975–127824976	acceptor_loss	1.0000	4
9:127825229–127825230	donor_loss	1.0000	5
9:127825358–127825359	acceptor_loss	1.0000	4

AlphaMissense

840 missense substitutions predicted likely pathogenic (of 4,281 scored), across 258 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F530	8	0.923	0.991
F600	8	0.905	0.981
S649	8	0.897	0.993
S646	8	0.865	0.990
F532	8	0.852	0.970
F389	8	0.762	0.951
C493	7	0.975	0.988
C549	7	0.971	0.988
C394	7	0.969	0.986
C412	7	0.966	0.985
C442	7	0.961	0.985
C363	7	0.957	0.985
C382	7	0.956	0.989
W261	7	0.955	0.992
F460	7	0.953	0.979
C207	7	0.938	0.969
C350	7	0.933	0.965
S643	7	0.902	0.992
N423	7	0.897	0.963
C182	7	0.896	0.937

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.31e-07
Liver Hepatocellular Carcinoma (TCGA)	favorable	1.53e-05
Kidney Renal Clear Cell Carcinoma (validation)	favorable	7.87e-05
Liver Hepatocellular Carcinoma (validation)	favorable	0.00028
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000745

Disease associations

OMIM: gene MIM:131195 | disease phenotypes: MIM:187300, MIM:174900, MIM:178600, MIM:108010

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
telangiectasia, hereditary hemorrhagic, type 1	Definitive	Autosomal dominant	3
hereditary hemorrhagic telangiectasia	Strong	Autosomal dominant	2
juvenile polyposis syndrome	Limited	Autosomal dominant

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

2 validity classifications:

Disease	Classification	Inheritance
juvenile polyposis syndrome	Limited	AD
telangiectasia, hereditary hemorrhagic, type 1	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 7 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
Bleeding and platelet disorders	green
Cerebral vascular malformations	green
Fetal anomalies	green
Hereditary haemorrhagic telangiectasia	green
Inherited bleeding disorders	green
Pulmonary arterial hypertension	green
Vascular skin disorders	green

Mondo (6): hereditary hemorrhagic telangiectasia (MONDO:0019180), telangiectasia, hereditary hemorrhagic, type 1 (MONDO:0008535), juvenile polyposis syndrome (MONDO:0017380), pulmonary arterial hypertension (MONDO:0015924), pulmonary hypertension, primary, 1 (MONDO:0024533), arteriovenous malformations of the brain (MONDO:0007154)

Orphanet (5): Hereditary hemorrhagic telangiectasia (Orphanet:774), Juvenile polyposis syndrome (Orphanet:2929), Pulmonary arterial hypertension (Orphanet:182090), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), Brain arteriovenous malformation (Orphanet:46724)

HPO phenotypes

showing 60 of 89 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000214	Lip telangiectasia
HP:0000227	Tongue telangiectasia
HP:0000421	Epistaxis
HP:0000434	Nasal mucosa telangiectasia
HP:0000471	Gastrointestinal angiodysplasia
HP:0000524	Conjunctival telangiectasia
HP:0000822	Hypertension
HP:0000961	Cyanosis
HP:0000969	Edema
HP:0001009	Telangiectasia
HP:0001017	Anemic pallor
HP:0001123	Visual field defect
HP:0001217	Clubbing
HP:0001232	Nail bed telangiectasia
HP:0001250	Seizure
HP:0001269	Hemiparesis
HP:0001342	Cerebral hemorrhage
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001510	Growth delay
HP:0001635	Congestive heart failure
HP:0001694	Right-to-left shunt
HP:0001722	High-output congestive heart failure
HP:0001892	Abnormal bleeding
HP:0001901	Polycythemia
HP:0001903	Anemia
HP:0002040	Esophageal varix
HP:0002076	Migraine
HP:0002091	Restrictive ventilatory defect
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002105	Hemoptysis
HP:0002138	Subarachnoid hemorrhage
HP:0002140	Ischemic stroke
HP:0002170	Intracranial hemorrhage
HP:0002204	Pulmonary embolism
HP:0002239	Gastrointestinal hemorrhage
HP:0002248	Hematemesis
HP:0002249	Melena
HP:0002326	Transient ischemic attack
HP:0002363	Abnormal brainstem morphology
HP:0002390	Spinal arteriovenous malformation
HP:0002408	Cerebral arteriovenous malformation
HP:0002573	Hematochezia
HP:0002604	Gastrointestinal telangiectasia
HP:0002616	Aortic root aneurysm
HP:0002621	Atherosclerosis
HP:0002626	Venous varicosities of celiac and mesenteric vessels
HP:0002629	Gastrointestinal arteriovenous malformation
HP:0002642	Arteriovenous fistulas of celiac and mesenteric vessels
HP:0002647	Aortic dissection
HP:0002707	Palate telangiectasia
HP:0002875	Exertional dyspnea
HP:0004394	Multiple gastric polyps
HP:0004406	Spontaneous, recurrent epistaxis
HP:0004783	Duodenal polyposis
HP:0004936	Venous thrombosis
HP:0005227	Adenomatous colonic polyposis

GWAS associations

4 associations:

Study	Trait	p-value
GCST005951_75	Body mass index	5e-9
GCST90002393_88	Monocyte count	6e-9
GCST006585_1099	Blood protein levels	8e-9
GCST000753_14	Metabolic syndrome	1e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0000195	metabolic syndrome
EFO:0006336	diastolic blood pressure
EFO:0004340	body mass index
EFO:0005091	monocyte count

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
D013683	Telangiectasia, Hereditary Hemorrhagic	C14.907.454.900; C14.907.823.780; C15.378.463.515.900; C16.131.240.850.968

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712885 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ENG protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
CAROTUXIMAB	Antibody	3

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1800956	methotrexate	Metabolism/PK	Allele G is associated with decreased clearance of methotrexate in children with Acute lymphoblastic leukemia as compared to allele C.	PMID:39611166

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
carotuximab	Binding	9.0	pKd

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cadmium	decreases expression, decreases reaction, increases abundance, increases palmitoylation	2
Tobacco Smoke Pollution	decreases expression	2
Cadmium Chloride	decreases expression, decreases reaction, increases abundance, increases palmitoylation	2
Raloxifene Hydrochloride	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
napabucasin	decreases expression	1
mivebresib	decreases expression	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
bisphenol A	increases expression	1
deoxynivalenol	decreases expression	1
salinomycin	decreases expression	1
hydroxyhydroquinone	decreases reaction, decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
perfluorooctanoic acid	decreases expression	1
tobacco tar	decreases expression, decreases reaction	1
benzo(e)pyrene	increases methylation	1
4-aminobenzhydrazide	decreases expression, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
Y 27632	decreases expression	1
3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1

Cellosaurus cell lines

9 cell lines: 6 transformed cell line, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1R9	Abcam HeLa ENG KO	Cancer cell line	Female
CVCL_B9XR	Abcam THP-1 ENG KO	Cancer cell line	Male
CVCL_C6ZL	Abcam PC-3 ENG KO	Cancer cell line	Male
CVCL_GT60	GM10232	Transformed cell line	Male
CVCL_W903	GM10228	Transformed cell line	Male
CVCL_W904	GM10231	Transformed cell line	Female
CVCL_W905	GM10249	Transformed cell line	Male
CVCL_W906	GM10711	Transformed cell line	Female
CVCL_W907	GM10715	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT05421312	Phase 4	UNKNOWN	Periarticular Penetration of Cefazolin and Clindamycin in Second Stage Revision Arthroplasty of the Hip
NCT02389959	Phase 4	COMPLETED	Intranasal Bevacizumab for HHT-Related Epistaxis
NCT00058929	Phase 4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	Phase 4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	Phase 4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	Phase 4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	Phase 4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	Phase 4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	Phase 4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	Phase 4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	Phase 4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	Phase 4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	Phase 4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	Phase 4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	Phase 4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	Phase 4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	Phase 4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	Phase 4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	Phase 4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	Phase 4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	Phase 4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	Phase 4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	Phase 4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	Phase 4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	Phase 4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	Phase 4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	Phase 4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	Phase 4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	Phase 4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	Phase 4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	Phase 4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	Phase 4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	Phase 4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	Phase 4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	Phase 4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	Phase 4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	Phase 4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	Phase 4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	Phase 4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	Phase 4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	Phase 4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	Phase 4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial
NCT03497689	Phase 4	COMPLETED	EXPEDITE: A Study of Remodulin Induction Followed by Orenitram Optimization to Treat Pulmonary Arterial Hypertension
NCT04435782	Phase 4	TERMINATED	A Study of Selexipag Assessing Right Ventricular Remodeling in Pulmonary Arterial Hypertension by Cardiac Magnetic Resonance Imaging
NCT04955990	Phase 4	TERMINATED	A Study of Real-world Cohort of Pulmonary Arterial Hypertension (PAH) Participants
NCT05203510	Phase 4	ACTIVE_NOT_RECRUITING	A Study of a Mean Pulmonary Artery Pressure-Targeted Approach With Early and Rapid Treprostinil Therapy to Reverse Right Ventricular Remodeling in Participants With Pulmonary Arterial Hypertension
NCT05439460	Phase 4	COMPLETED	Management of Acute Pulmonary Hypertensive Crisis in Children With Known Pulmonary Arterial Hypertension
NCT05825417	Phase 4	ACTIVE_NOT_RECRUITING	Pulmonary Hypertension: Intensification and Personalisation of Combination Rx
NCT05828147	Phase 4	UNKNOWN	Anti-CD20 Antibodies for Treatment of SLE-PAH
NCT06025916	Phase 4	RECRUITING	Postpartum Hemorrhage Reduction With Oral Tranexamic Acid: a Clinical Trial
NCT06317805	Phase 4	RECRUITING	Initial Triple Therapy Including Parenteral Treprostinil vs Initial Double Oral Therapy in PAH Group I Patients
NCT06409026	Phase 4	COMPLETED	Sotatercept on Central Cardiopulmonary Performance and Peripheral Oxygen Transport During Exercise in Pulmonary Arterial Hypertension
NCT06605326	Phase 4	COMPLETED	Subcutaneous Treprostinil as a Bridge to Lung Transplantation in Severe Pulmonary Hypertension: A Single-Arm Retrospective Study
NCT06658522	Phase 4	RECRUITING	Right Ventricular Compensation With Sotatercept: A Prospective Single Arm Open Label Phase 4 Study to Evaluate the Effects of Sotatercept on Right Ventricular Function in Pulmonary Arterial Hypertension (RECOMPENSE)
NCT06671990	Phase 4	NOT_YET_RECRUITING	The CardioMEMS Vericiguat Heart Failure Trial
NCT07600723	Phase 4	NOT_YET_RECRUITING	A Study of Sotatercept (MK-7962) in People With Pulmonary Arterial Hypertension (PAH) in India (MK-7962-037)
NCT07713914	Phase 4	RECRUITING	Randomized Study of Triple Therapy vs Sildenafil Dose Optimization in Pulmonary Arterial Hypertension
NCT07759804	Phase 4	NOT_YET_RECRUITING	A Study of Inhaled Treprostinil (LIQ861) in Adults With Pulmonary Arterial Hypertension Transitioning From Oral Selexipag
NCT00004654	Phase 3	COMPLETED	Phase III Randomized, Placebo-Controlled, Crossover Study of Soy Protein Isolate for Hereditary Hemorrhagic Telangiectasia
NCT00355108	Phase 3	COMPLETED	ATERO : A Randomised Study With Tranexamic Acid in Epistaxis of Rendu Osler Syndrome