rs28936687 — ACVRL1

Pathogenic missense variant in ALK1 kinase domain causing hereditary hemorrhagic telangiectasia type 2 (HHT2) and pulmonary arterial hypertension

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ALK1 Gly211Asp — A Kinase Domain Variant That Opens Arteries Where None Should Form

The ACVRL1 gene encodes ALK111 ALK1
Activin receptor-like kinase 1, also written ACVRL1 — a serine/threonine kinase receptor expressed predominantly on vascular endothelial cells throughout the body, a receptor that sits on the surface of blood vessel lining cells and binds the growth factors BMP9 and BMP1022 BMP9 and BMP10
Bone morphogenetic proteins 9 and 10 — despite their names, these proteins are key regulators of vascular development and stability, not just bone growth. When ALK1 is working normally, this BMP9/BMP10 signaling keeps blood vessel walls stable and prevents aberrant vessel sprouting. When one copy of ACVRL1 carries a pathogenic variant like Gly211Asp, vascular stability breaks down — small arteriovenous connections form and enlarge into arteriovenous malformations33 arteriovenous malformations
AVMs — direct artery-to-vein connections that bypass the capillary bed. Blood under arterial pressure floods directly into veins, causing rupture, shunting, and downstream organ damage in the nose, skin, lungs, liver, and brain.

This condition is called hereditary hemorrhagic telangiectasia type 244 hereditary hemorrhagic telangiectasia type 2
HHT2, also known as Rendu-Osler-Weber syndrome — a rare autosomal dominant vascular disorder affecting approximately 1 in 5,000 people worldwide. A single pathogenic ACVRL1 allele is sufficient to cause HHT2, and nearly all carriers will develop some disease manifestation over a lifetime, though severity varies considerably even within the same family.

The Mechanism

Gly211 sits within the kinase domain of ALK1, the enzymatic core that phosphorylates downstream signaling proteins (SMAD1/5/8) when BMP9 or BMP10 binds. Glycine's small, flexible structure at this conserved position is essential for maintaining the correct geometry of the kinase active site. Replacing glycine with the larger, charged aspartic acid (p.Gly211Asp, c.631G>A) disrupts the catalytic pocket, impairing or abolishing kinase activity. The result is a loss-of-function allele55 loss-of-function allele
haploinsufficiency — having 50% of normal ALK1 signaling is insufficient to maintain normal vascular endothelial quiescence. ACVRL1 pathogenic missense variants are concentrated at highly conserved residues; Gly211 shows strong evolutionary conservation, consistent with essential structural function.

Without adequate ALK1 signaling, endothelial cells over-proliferate and fail to suppress angiogenic sprouting, creating the direct artery-to-vein connections characteristic of HHT.

The Evidence

The French-Italian HHT network study66 French-Italian HHT network study
Lesca et al., Genet Med, 2007 — multicenter genotype-phenotype analysis comparing 239 HHT1 (ENG) and HHT2 (ACVRL1) patients established key clinical distinctions between HHT subtypes. HHT2 (ACVRL1) shows symptomatic pulmonary AVMs in 5.2% of patients (vs 34.4% in HHT1), but hepatic AVM involvement is found almost exclusively in HHT2, and gastrointestinal bleeding is more frequent (16.4% vs 6.5%). Cerebral abscess from paradoxical embolism through pulmonary AVMs occurred in 0.8% of HHT2 vs 7.5% of HHT1 patients.

The Second International HHT Guidelines77 Second International HHT Guidelines
Faughnan et al., Ann Intern Med, 2020 — 36 recommendations from 42 international experts covering screening, bleeding management, pregnancy, and pediatric care recommend systematic vascular screening for all HHT gene carriers, starting in childhood. Antifibrinolytics (tranexamic acid) and antiangiogenic therapy (bevacizumab) are now guideline-recommended for bleeding management. A randomized phase 2 trial88 randomized phase 2 trial
Dupuis-Girod et al., J Intern Med, 2023 — 24 patients, bevacizumab vs placebo; hemoglobin significantly improved at 6 months in bevacizumab group (p=0.02) supports IV bevacizumab for severe HHT-related anemia.

ClinVar classifies the G>A allele (Gly211Asp) as Pathogenic/Likely Pathogenic for both HHT2 and pulmonary arterial hypertension related to HHT (variation ID 23292).

Practical Actions

Carriers of this variant require proactive surveillance. Pulmonary AVMs warrant transthoracic contrast echocardiography (bubble echo) every 3–5 years; even in HHT2, where pulmonary AVMs are less frequent than HHT1, the risk of paradoxical stroke or cerebral abscess from shunting is real. Brain MRI is recommended during childhood and again by age 18–20 to screen for cerebral AVMs. Adults need hepatic imaging to detect liver AVMs, which are more prevalent in HHT2. Recurrent epistaxis — often the earliest symptom, typically beginning in the second decade of life — should prompt iron studies and supplementation ahead of symptomatic anemia.

Interactions

ACVRL1 loss-of-function mutations interact biologically with the ENG (endoglin) and SMAD4 pathways, which operate in the same BMP signaling cascade. Concurrent pathogenic variants in SMAD4 (rs387907257 and related) cause a combined HHT-juvenile polyposis syndrome requiring additional gastrointestinal cancer surveillance beyond standard HHT management. Carriers of ACVRL1 pathogenic variants who also develop pulmonary arterial hypertension (a recognized complication) may need BMPR2 pathway evaluation, as ACVRL1 and BMPR2 share signaling converging on SMAD1/5/8.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No ACVRL1 Gly211Asp variant detected

You carry two copies of the reference allele at rs28936687. The Gly211Asp pathogenic variant in ACVRL1 is not present in your genome. This variant is extremely rare globally — fewer than 1 in 10,000 people carry it — and its absence means your ALK1 kinase signaling at this residue is unaffected by this specific mutation. Hereditary hemorrhagic telangiectasia type 2 due to this variant does not apply to you.

AG HHT2 Carrier High Risk

Pathogenic ACVRL1 variant — one copy sufficient to cause HHT2

ACVRL1 encodes ALK1, a receptor expressed on vascular endothelial cells that binds the angiogenic regulators BMP9 and BMP10. Gly211 sits in the kinase domain active site; the Asp substitution disrupts the catalytic geometry, abolishing or severely impairing kinase function. The result is haploinsufficiency — 50% of normal ALK1 signaling is insufficient to keep endothelial cells quiescent, leading to uncontrolled vascular sprouting and AVM formation.

HHT2 (ACVRL1) differs from HHT1 (ENG) in important ways: hepatic AVMs are nearly exclusive to HHT2 and may cause high-output cardiac failure or biliary ischemia; pulmonary AVMs, while less frequent than in HHT1 (symptomatic in ~5%, detectable asymptomatic in ~13%), still carry stroke and cerebral abscess risk via paradoxical embolism. Gastrointestinal bleeding from telangiectasias occurs in ~16% of HHT2 patients. Penetrance increases with age; epistaxis typically begins in the second decade.

ClinVar variation ID: 23292 — Pathogenic/Likely Pathogenic (HHT2 and PAH related to HHT). Second International HHT Guidelines (Ann Intern Med 2020) provide the current standard of care for surveillance and treatment.

AA Homozygous (Theoretical) Homozygous

Two copies of the pathogenic ACVRL1 variant — extremely rare, very severe expected phenotype

ACVRL1 heterozygous loss-of-function produces HHT2 through haploinsufficiency — one functional copy is insufficient for normal vascular endothelial regulation. Complete ALK1 deficiency in mouse models results in embryonic lethality from vascular defects, suggesting that biallelic loss in humans would produce a very severe or possibly incompatible-with-life phenotype. No confirmed adult homozygotes for this specific variant are documented in ClinVar or the published literature. If reported in a clinical or research context, genotyping artifacts (e.g., PCR dropout of one allele) should be excluded before clinical conclusions are drawn.