ACVRL1

Chr 12AD

activin A receptor like type 1

NCBI Gene: 94ENSG00000139567UniProt: P37023

Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well

Primary Disease Associations & Inheritance

Telangiectasia, hereditary hemorrhagic, type 2MIM #600376
AD
594
ClinVar variants
252
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— ACVRL1
🧬
Gene-Disease Validity (ClinGen)
telangiectasia, hereditary hemorrhagic, type 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
252 Pathogenic / Likely Pathogenic· 149 VUS of 594 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.69LOEUF
pLI 0.001
Z-score 2.66
OE 0.40 (0.24–0.69)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.45Z-score
OE missense 0.61 (0.54–0.69)
190 obs / 311.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.40 (0.24–0.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.54–0.69)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 9 / 22.7Missense obs/exp: 190 / 311.5Syn Z: -0.45

ClinVar Variant Classifications

594 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic155
Likely Pathogenic97
VUS149
Likely Benign156
Benign10
Conflicting27
155
Pathogenic
97
Likely Pathogenic
149
VUS
156
Likely Benign
10
Benign
27
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
70
40
45
0
155
Likely Pathogenic
26
61
10
0
97
VUS
2
121
21
5
149
Likely Benign
0
7
36
113
156
Benign
0
0
10
0
10
Conflicting
—27
Total98229122118594

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

View in ClinVar →

Protein Context — Lollipop Plot

ACVRL1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ACVRL1-related hereditary haemorrhagic telangiectasia

definitive
ADLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Telangiectasia, hereditary hemorrhagic, type 2

MIM #600376

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ACVRL1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Hereditary haemorrhagic telangiectasia.
Hermann R et al.·Nat Rev Dis Primers
2025Review
Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2).
McDonald J et al.·Genet Med
2020
Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist's perspective.
Kritharis A et al.·Haematologica
2018Review
Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia.
Shovlin CL et al.·Blood
2020
Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.
Welch CL et al.·Genet Med
2023
Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.
Zhao S et al.·Nat Commun
2023
[Hereditary hemorrhagic telangiectasia].
Parrot A et al.·Rev Mal Respir
2023Review
Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes-ENG and ACVRL1.
DeMille D et al.·Hum Mutat
2024
Genetics of pulmonary hypertension.
Best DH et al.·Curr Opin Cardiol
2014Review
Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.
Park HK et al.·Ann Neurol
2023Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Modulating ACVRL1 Expression in HMEC1 Cells as a Simplified In Vitro Model for Hereditary Hemorrhagic Telangiectasia (HHT) Type 2 Studies.
Rusche JR et al.·In Vivo
2026🔓 Open AccessFunctional
Multiple lesion-specific somatic mutations and bi-allelic loss of ACVRL1 in a single patient with hereditary haemorrhagic telangiectasia.
Darre Haahr P et al.·Eur J Hum Genet
2026🔓 Open Access
Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in ENG and ACVRL1.
Anzell AR et al.·Circ Genom Precis Med
2025
Generation of patient-derived and gene-corrected hiPSC lines from Hereditary Hemorrhagic Telangiectasia type 2 patients with ACVRL1 c.1042delG mutation.
Urdaneta KE et al.·Stem Cell Res
2025Cohort
Targeted proteomic analysis identifies ACVRL1 as a marker of cerebral edema in aneurysmal subarachnoid hemorrhage.
Yang BSK et al.·J Cereb Blood Flow Metab
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Hereditary Hemorrhagic Telangiectasia

Influence of Hypoxic Induced Factors in Patients With Hereditary Hemorrhagic Telangiectasia

RECRUITING
NCT04469517University Hospital, EssenStarted 2020-08-10
hypoxic induced factors
Heart Defects, CongenitalPulmonary Arterial HypertensionGenetic Testing

Genes Associated With Development of Pulmonary Arterial Hypertension in Patients With Congenital Shunt Lesions

RECRUITING
NCT02691689Phase NAUniversitaire Ziekenhuizen KU LeuvenStarted 2015-11
Genetic testing
Hereditary Hemorrhagic Telangiectasia

Cardiac Evaluation in Hereditary Hemorrhagic Telangiectasia

NOT YET RECRUITING
NCT07101575Fondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-08-05
Transthoracic echocardiography

External Resources

Links to major genomics databases and tools