Pulmonary arterial hypertension: genes and variants

Genes linked to Pulmonary arterial hypertension

• BMPR2: Bone morphogenetic protein receptor type-2

  It initiates BMP signaling in vascular cells and helps maintain normal pulmonary-artery structure and endothelial function. Heterozygous loss-of-function variants are the most common known genetic cause of heritable pulmonary arterial hypertension.

  29 disease-causing and 21 uncertain variants in BMPR2 are linked to Pulmonary arterial hypertension.

• ACVRL1: Activin receptor type-1-like

  It mediates BMP9 and BMP10 signaling in vascular endothelial cells and helps maintain normal vessel maturation and quiescence. Heterozygous loss-of-function variants cause hereditary hemorrhagic telangiectasia type 2, with telangiectasias and arteriovenous malformations.

  3 disease-causing and 0 uncertain variants in ACVRL1 are linked to Pulmonary arterial hypertension.

• EIF2AK4: eIF-2-alpha kinase GCN2

  It senses amino-acid deprivation and other stresses and reduces global translation through phosphorylation of eIF2alpha. Biallelic loss-of-function variants are a major cause of pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease.

  0 disease-causing and 0 uncertain variants in EIF2AK4 are linked to Pulmonary arterial hypertension.

• EDNRB: Endothelin receptor type B

  0 disease-causing and 0 uncertain variants in EDNRB are linked to Pulmonary arterial hypertension.

• BMPR1A: Bone morphogenetic protein receptor type-1A

  It transduces BMP signals that regulate epithelial growth, differentiation, and tissue patterning through SMAD proteins and other pathways. Germline loss-of-function variants cause juvenile polyposis syndrome and can substantially increase gastrointestinal cancer risk.

  0 disease-causing and 5 uncertain variants in BMPR1A are linked to Pulmonary arterial hypertension.

• ABCC8: ATP-binding cassette sub-family C member 8

  It senses cellular nucleotide levels as the regulatory component of pancreatic beta-cell ATP-sensitive potassium channels and thereby couples glucose metabolism to insulin secretion. Loss-of-function variants cause congenital hyperinsulinism, whereas activating variants can cause neonatal diabetes.

  0 disease-causing and 6 uncertain variants in ABCC8 are linked to Pulmonary arterial hypertension.

Weakly linked (only a few uncertain records): PHF6.

Where Pulmonary arterial hypertension variants cluster

• BMPR2 Protein kinase (positions 203–504): 20 of 29 disease-causing changes, 2.4× more than its size predicts.
• BMPR2 Extracellular (positions 27–150): 9 of 29 disease-causing changes, 2.6× more than its size predicts.

Known disease-causing variants in Pulmonary arterial hypertension

Which prediction tools work for Pulmonary arterial hypertension

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 92 out of 100

Same protein, different disease

• Pulmonary hypertension, primary, 1 is also caused by BMPR2 variants; they fall partly in the same places as the Pulmonary arterial hypertension variants (38 disease-causing).
• Primary pulmonary hypertension is also caused by BMPR2 variants; they fall in the same places as the Pulmonary arterial hypertension variants (13 disease-causing).
• Telangiectasia, hereditary hemorrhagic, type 2 is also caused by ACVRL1 variants; they fall mostly in different places as the Pulmonary arterial hypertension variants (178 disease-causing).
• Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia is also caused by ACVRL1 variants; they fall mostly in different places as the Pulmonary arterial hypertension variants (6 disease-causing).
• Hereditary hemorrhagic telangiectasia is also caused by ACVRL1 variants; they fall mostly in different places as the Pulmonary arterial hypertension variants (4 disease-causing).

Diseases related to Pulmonary arterial hypertension

• Pulmonary hypertension, primary, 1, also linked to ACVRL1 and BMPR2
• Monogenic diabetes, also linked to ABCC8
• Hereditary factor VIII deficiency disease, also linked to ACVRL1
• Telangiectasia, hereditary hemorrhagic, type 2, also linked to ACVRL1
• Maturity-onset diabetes of the young, also linked to ABCC8
• Type 2 diabetes mellitus, also linked to ABCC8
• Hyperinsulinemic hypoglycemia, familial, 1, also linked to ABCC8
• Waardenburg syndrome, also linked to EDNRB
• Atrial septal defect, also linked to ABCC8
• Diabetes mellitus, permanent neonatal 3, also linked to ABCC8
• Neonatal diabetes mellitus, also linked to ABCC8
• Familial hyperinsulinism, also linked to ABCC8

Frequently asked questions

Which genes are linked to Pulmonary arterial hypertension?

In CATVariant, Pulmonary arterial hypertension is linked to 6 analyzed proteins: BMPR2 (Bone morphogenetic protein receptor type-2), ACVRL1 (Activin receptor type-1-like), EIF2AK4 (eIF-2-alpha kinase GCN2), EDNRB (Endothelin receptor type B), BMPR1A (Bone morphogenetic protein receptor type-1A) and ABCC8 (ATP-binding cassette sub-family C member 8).

How many genetic variants are linked to Pulmonary arterial hypertension?

101 variants: 32 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 33 are of uncertain significance or have conflicting reports.

Which uncertain variants in Pulmonary arterial hypertension look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Pulmonary arterial hypertension?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 32 disease-causing and 110 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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