ACVRL1

Chr 12AD

activin A receptor like type 1

Also known as: ACVRLK1, ALK-1, ALK1, HHT, HHT2, ORW2, SKR3, TSR-I

NCBI Gene: 94 ENSG00000139567 UniProt: P37023 OMIM: 601284

This gene encodes ALK1, a type I transmembrane serine/threonine kinase receptor that binds TGF-beta family ligands BMP9 and BMP10 to regulate normal blood vessel development through SMAD transcriptional activation. Mutations cause hereditary hemorrhagic telangiectasia type 2 (Rendu-Osler-Weber syndrome), an autosomal dominant vascular disorder characterized by abnormal blood vessel formation leading to telangiectasias and arteriovenous malformations. The gene shows high tolerance to loss-of-function variants (pLI 0.001, LOEUF 0.69), suggesting complete loss of function may not be the primary disease mechanism in affected patients.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.691 OMIM phenotype

Clinical Summary— ACVRL1

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Gene-Disease Validity (ClinGen)

telangiectasia, hereditary hemorrhagic, type 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

250 unique Pathogenic / Likely Pathogenic· 169 VUS of 597 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ACVRL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.001

Z-score 2.66

OE 0.40 (0.24–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

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?

LoF OE?0.40 (0.24–0.69)

0≤0.351.4

Missense OE?0.61 (0.54–0.69)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 9 / 22.7Missense obs/exp: 190 / 311.5Syn Z: -0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveACVRL1-related hereditary haemorrhagic telangiectasiaLOFAD

This gene — mechanism propensity

0.7228th %ile

GOF

0.77top 25%

LOF

0.3164th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 55% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median · 1 literature citation

GOFprediction 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.

Literature Evidence

DNHere we show that some of the HHT2-related mutations generate a dominant-negative effect whereas the others give rise to a null phenotype via loss of protein expression or receptor activity.1

LOFMany mutations have been identified in ENG and ACVRL1 genes and support the haploinsufficiency model for HHT.2

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

References

ClinVar Variant Classifications

597 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic153

Likely Pathogenic97

VUS169

Likely Benign141

Benign8

Conflicting23

153

Pathogenic

Likely Pathogenic

169

VUS

141

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	109	34	10	0	153
Likely Pathogenic	29	63	5	0	97
VUS	3	143	18	5	169
Likely Benign	0	6	37	98	141
Benign	0	0	8	0	8
Conflicting	—				23
Total	141	246	78	103	591

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

View in ClinVar →

2 pathogenic / likely-pathogenic (of 3) ClinVar copy-number / structural variants overlap ACVRL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →