ACVRL1

Chr 12

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

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.

ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismLOEUF 0.69

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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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE0.40 (0.24–0.69)

0≤0.351.4

Missense OE0.61 (0.54–0.69)

0≤0.61.4

Synonymous OE1.05

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

0.7228th %ile

GOF

0.77top 25%

LOF

0.3164th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-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 dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOF1 literature citation

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.PMID:16282348

LOFMany mutations have been identified in ENG and ACVRL1 genes and support the haploinsufficiency model for HHT.PMID:15879500

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.