rs1060502576 — BMPR2

Rare stop-gain variant in BMPR2 (p.Trp466Ter) that truncates the kinase domain via nonsense-mediated decay, causing haploinsufficiency and hereditary pulmonary arterial hypertension with incomplete penetrance and sex-dependent expression

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BMPR2 W466* — A Silenced Receptor and the Quiet Rise of Pulmonary Pressure

The tiny arteries that carry blood through the lungs depend on a protein called BMPR211 BMPR2
Bone Morphogenetic Protein Receptor Type 2 — a transmembrane kinase receptor on pulmonary vascular endothelial and smooth muscle cells that relays anti-proliferative BMP signals into the cell, restraining abnormal arterial wall growth. When active, it phosphorylates SMAD1/5/8 proteins that suppress smooth muscle proliferation. to suppress abnormal muscle growth in the pulmonary artery walls. When this receptor is absent or defective, the pulmonary arteries gradually narrow — a process called pulmonary arterial hypertension (PAH) — forcing the right ventricle to pump against ever-increasing resistance until it fails. The BMPR2 c.1398G>A variant (p.Trp466Ter) replaces the codon for tryptophan at position 466 with a premature stop signal, truncating the protein in the kinase domain and eliminating it through nonsense-mediated mRNA decay22 nonsense-mediated mRNA decay
NMD — a cellular quality-control mechanism that destroys mRNAs carrying premature stop codons before they can be translated into truncated and potentially harmful proteins. Activation of NMD in this case leaves only the intact BMPR2 allele to produce functional receptor. (NMD).

BMPR2 pathogenic variants are the most common hereditary cause of PAH, accounting for over 75% of familial PAH cases and 15–25% of apparently sporadic (idiopathic) cases. The W466* stop-gain is classified Pathogenic in ClinVar (allele ID 392288) across four independent submissions, all linking to conditions including Pulmonary hypertension, primary, 1 (PPH1) and Pulmonary arterial hypertension. The variant is present in only one allele out of approximately 805,810 exomes sequenced in gnomAD v4 — exclusively in individuals of European ancestry — consistent with its pathogenic nature and strong negative selection.

The Mechanism

BMPR2 encodes a transmembrane receptor that, when activated by bone morphogenetic protein (BMP) ligands — particularly BMP9 and BMP10 — phosphorylates intracellular SMAD1/5/8 proteins and restrains the proliferation of pulmonary arterial smooth muscle cells and maintains endothelial integrity. Trp466 lies within the intracellular kinase domain; a premature stop at this position destroys the entire catalytic kinase module. The mutant transcript is degraded by NMD, leaving only the intact allele — a state of haploinsufficiency33 haploinsufficiency
Having only one functional copy of a gene when two copies are needed for adequate protein levels. For BMPR2, one copy produces roughly 50% of normal receptor density, which is insufficient to maintain pulmonary vascular homeostasis in a subset of carriers under the right conditions..

A 2026 mechanistic study demonstrated directly that a ~50% reduction in BMPR2 protein levels44 ~50% reduction in BMPR2 protein levels
Chu KY et al., Cells 2026 — used siRNA to reduce BMPR2 to levels mimicking haploinsufficiency in primary human pulmonary artery endothelial cells; BMP9/10 signaling responses were measured by SMAD phosphorylation and proliferation assays attenuates BMP9/10-induced SMAD1/5/8 activation and abolishes proliferative survival responses in pulmonary artery endothelial cells — establishing that haploinsufficiency alone is sufficient to compromise the pulmonary vascular endothelium's BMP signaling homeostasis.

Unlike missense BMPR2 variants, which produce a malfolded protein capable of poisoning the normal receptor through dominant-negative interference, NMD-positive truncating mutations like W466* leave only simpler haploinsufficiency. This molecular distinction has clinical consequences: carriers of truncating BMPR2 variants tend to develop PAH at older ages and with less extreme hemodynamic compromise than missense mutation carriers.

The Evidence

Truncating vs missense severity: Austin et al., Respiratory Research, 200955 Austin et al., Respiratory Research, 2009
Compared 169 heritable PAH patients by mutation type; truncating mutation carriers were predominantly symptomatic after age 36, while missense mutation carriers clustered before age 36; the hemodynamic severity difference was statistically significant in female carriers showed that carriers of truncating mutations (such as W466*) develop PAH later and with milder hemodynamics than missense carriers, consistent with haploinsufficiency rather than dominant-negative disruption of the remaining normal receptor.

Survival impact: The largest available evidence comes from an individual participant data meta-analysis of 1,550 PAH patients across eight cohorts66 individual participant data meta-analysis of 1,550 PAH patients across eight cohorts
Evans JDW et al., Lancet Respir Med, 2016 — 448 (29%) carried any pathogenic BMPR2 variant; analysis age- and sex-adjusted, in which BMPR2 mutation carriers had a 42% higher hazard of death or lung transplantation (HR 1.42, 95% CI 1.15–1.75) and 27% higher all-cause mortality (HR 1.27) than non-carriers. Carriers presented at a mean age of 35.4 years versus 42.0 years in non-carriers, and showed markedly lower vasodilator responsiveness (3% vs 16%), which affects treatment options.

Hemodynamic burden: A 2025 meta-analysis of 17 studies (2,190 patients)77 2025 meta-analysis of 17 studies (2,190 patients)
Wu J et al., Resp Research 2025 — systematic review comparing hemodynamic profiles at diagnosis stratified by BMPR2 mutation status found that BMPR2 carriers had mean pulmonary artery pressure (mPAP) approximately 6.41 mmHg higher and pulmonary vascular resistance (PVR) 3.66 Wood units higher than non-carriers, with significantly reduced cardiac index and output.

Subclinical phenotype before diagnosis: Even before developing PAH, BMPR2 mutation carriers show measurable cardiac changes. The DELPHI phenotyping study88 DELPHI phenotyping study
Tóth EN et al., Eur Respir J, 2024 — 28 unaffected BMPR2 carriers vs 21 healthy controls; multimodal cardiac MRI and hemodynamic assessment; 4-year prospective follow-up found that carriers had significantly smaller right ventricular volumes, higher right ventricular afterload, and impaired ventricular-arterial coupling compared to controls — and 2 of 28 carriers developed PAH during the 4-year follow-up despite having normal BNP and echocardiography at the time of PAH diagnosis. This underscores the need for more sensitive screening than standard echo alone.

Screening in asymptomatic carriers: The DELPHI-2 study99 DELPHI-2 study
Montani D et al., Eur Respir J, 2021; 55 asymptomatic adults carrying BMPR2 mutations enrolled prospectively; annual multimodal screening protocol including echo, BNP, CPET, RHC on indication followed 55 asymptomatic BMPR2 carriers annually. Overall PAH incidence was 2.3% per year — 0.99% per year in males and 3.5% per year in females, reflecting sex-dependent penetrance. All cases detected through systematic screening were at low-risk stage and responded well to oral PAH-targeted therapy, demonstrating the clinical value of surveillance before symptom onset.

Lifetime risk of developing PAH with a BMPR2 pathogenic variant is approximately 14% in males and 42% in females. The higher penetrance in females may involve hormonal modulation of pulmonary vascular biology, including effects of estrogen and related metabolites on BMPR2 expression and endothelial function.

Practical Actions

Identifying a W466* carrier before PAH develops is the critical clinical opportunity: the DELPHI-2 study showed that carriers detected by screening are at low-risk stage and respond to oral monotherapy, whereas symptomatic patients typically present with advanced disease and worse prognosis. Annual echocardiographic screening is the current minimum standard; right heart catheterization is indicated when screening raises concern or symptoms develop. The variant's truncating nature implies haploinsufficiency, not dominant-negative toxicity — this distinction is clinically relevant for emerging BMPR2-restoration therapies (sotatercept, tacrolimus) currently in trials that aim to augment residual BMPR2 signaling.

Each first-degree biological relative has a 50% chance of inheriting the W466* variant. Cascade genetic testing identifies relatives who need surveillance before symptoms develop.

Interactions

The companion BMPR2 variant rs1060502581 (R321*, p.Arg321Ter) is a distinct stop-gain in the same gene via the same haploinsufficiency mechanism. Both W466* and R321* are NMD-positive truncating mutations; compound heterozygosity for two BMPR2 loss-of-function alleles would be expected to cause more severe or earlier-onset PAH, though documented compound BMPR2 heterozygotes are extremely rare given the ultra-low population frequency of each variant.

Other PAH-associated genes — ACVRL1/ALK1 (rs28936687), ENG (endoglin), SMAD9, CAV1, KCNK3, GDF2/BMP9 (rs200330818) — act within the same BMP-SMAD signaling pathway and can modify penetrance. The "second hit" hypothesis for BMPR2 haploinsufficiency predicts that additional genetic, hormonal, or environmental insults (female sex, estrogen exposure, anorexigens, portal hypertension, HIV co-infection, hypoxia) are required for PAH to manifest clinically — explaining the incomplete penetrance seen even within families carrying identical BMPR2 pathogenic variants.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-Carrier Normal

No BMPR2 W466* variant — standard PAH risk from this mutation

You carry two copies of the normal BMPR2 sequence at this position and do not have the W466* stop-gain mutation. Your risk of hereditary pulmonary arterial hypertension from this specific variant is not elevated. The A allele is present in only one allele in approximately 805,810 exomes in gnomAD v4, and was observed exclusively in individuals of European ancestry — consistent with strong negative selection against this pathogenic variant. Other BMPR2 mutations and other PAH-associated genes are not captured by this result.

AG W466* Carrier High Risk

Carries one copy of BMPR2 W466* — hereditary PAH risk, requires cardiology evaluation

The c.1398G>A substitution (NM_001204.7) changes a TGG codon (tryptophan) to TGA (stop) at position 466 of the BMPR2 protein. Trp466 falls within the intracellular kinase domain (approximately residues 267–485 in BMPR2's canonical structure); truncation at this point destroys the downstream kinase machinery required for SMAD1/5/8 phosphorylation and anti-proliferative signal transduction.

Because the premature stop codon triggers nonsense-mediated mRNA decay, the mutant allele produces no protein product in most cell types. The remaining functional allele produces approximately 50% of normal BMPR2 receptor density — insufficient in some vascular contexts to maintain pulmonary homeostasis. A 2026 mechanistic study confirmed that mimicking this 50% reduction in human pulmonary artery endothelial cells attenuated BMP9/10-induced SMAD1/5/8 activation and abolished proliferative survival responses, establishing the direct cellular consequence of haploinsufficiency.

Unlike missense BMPR2 mutations (which produce a misfolded protein that also interferes with the normal receptor — a dominant-negative mechanism), truncating variants cause simpler haploinsufficiency: the severity of disease when it does occur is typically less extreme and onset is usually after age 36. However, once PAH is established, the long-term prognosis is substantially worse than in non-carrier PAH patients (HR 1.42 for death or transplantation in the Lancet Respir Med 2016 meta-analysis).

Clinical expression of PAH in carriers involves: - Exertional dyspnea, fatigue, and reduced exercise capacity (often the first symptoms) - Progressive right ventricular pressure overload detectable as elevated tricuspid regurgitation jet velocity and right ventricular enlargement on echocardiography - In advanced disease: syncope, lower-limb edema, hepatomegaly (right heart failure)

The lifetime PAH risk is substantially higher in females (42%) than males (14%), likely reflecting hormonal effects on pulmonary vascular biology and BMPR2 expression. However, affected females — once PAH is established — have better right ventricular adaptive capacity and treatment responses than males.

Approved PAH therapies (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostacyclin analogs, and the recently FDA-approved sotatercept) target the downstream vascular pathways; sotatercept in particular acts by sequestering TGF-β/activin ligands and may specifically benefit BMPR2 haploinsufficient patients by rebalancing SMAD signaling.

AA Homozygous W466* Homozygous

Carries two copies of BMPR2 W466* — biallelic loss of function, extremely rare

You carry two copies of the BMPR2 c.1398G>A stop-gain mutation, one on each chromosome 2. This is an exceptionally rare genotype — the A allele is present in only one allele out of approximately 805,810 gnomAD v4 exomes, and biallelic inheritance would require two carrier parents. BMPR2 is autosomal dominant: even a single copy of W466* is sufficient to confer hereditary PAH risk. Biallelic BMPR2 loss-of-function would eliminate all BMPR2 signaling capacity; whether this produces a more severe or qualitatively different phenotype than heterozygosity is not known from published homozygous case data. Management follows the same priorities as the heterozygous genotype, with immediate specialist referral, and the additional fact that all biological children will inherit at least one copy of W466*.