# NM_001204.7(BMPR2):c.240_241insT (p.Lys81Ter)

https://sugi.bio/variant/bmpr2-p-lys81ter

## Summary

**BMPR2 p.Lys81Ter (c.240_241insT)** is classified **Likely pathogenic** in BMPR2 (ClinVar, Expert panel, 4 submitters; last evaluated 2024-05-03). No gnomAD frequency available for this variant; Associated with pulmonary arterial hypertension.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs1085307183 · 4 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BMPR2 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to pulmonary arterial hypertension.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 593 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BMPR2 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Idiopathic/heritable pulmonary arterial hypertension** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pulmonary arterial hypertension — Very frequent (99-80%)
- Dyspnea — Frequent (79-30%)
- Abnormality of cardiovascular system physiology — Frequent (79-30%)
- Syncope — Occasional (29-5%)
- Palpitations — Occasional (29-5%)
- Hepatomegaly — Occasional (29-5%)
- Right ventricular dilatation — Occasional (29-5%)
- Tricuspid regurgitation — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007501/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BMPR2](https://sugi.bio/atlas/gene/BMPR2/) |
| Protein change (HGVS p.) | p.Lys81Ter |
| Coding change (HGVS c.) | c.240_241insT |
| MANE Select transcript | [NM_001204](https://www.ncbi.nlm.nih.gov/nuccore/NM_001204) |
| dbSNP | [rs1085307183](https://www.ncbi.nlm.nih.gov/snp/rs1085307183/) |
| Variant type | Insertion |
| Location | chr2:202464972-202464973 (GRCh38) |
| ClinVar | [VCV425725](https://www.ncbi.nlm.nih.gov/clinvar/variation/425725/) |

**All HGVS expressions:** `LRG_712:g.93646_93647insT`, `LRG_712t1:c.240_241insT`, `NC_000002.11:g.203329695_203329696insT`, `NC_000002.12:g.202464972_202464973insT`, `NG_009363.1:g.93646_93647insT`, `NM_001204.7:c.240_241insT`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.292, GERP -0.856, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.376, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BMPR2** population constraint: LOEUF 0.376, pLI 1, missense-Z 3.2823; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital heart disease** — Limited (AD)
- **pulmonary arterial hypertension** — Definitive (AD)

## Protein context {#protein}

Residue **81** lies in a disulfide bond; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 58.07, 27% of residues very-high.

**7 experimental structure(s)** (PDB): [2HLQ](https://www.rcsb.org/structure/2HLQ), [3G2F](https://www.rcsb.org/structure/3G2F), [6UNP](https://www.rcsb.org/structure/6UNP), [7PPA](https://www.rcsb.org/structure/7PPA), [7PPB](https://www.rcsb.org/structure/7PPB), [7PPC](https://www.rcsb.org/structure/7PPC).

## What this gene does {#gene-function}

*Describes the biological roles of BMPR2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BMPR2's established molecular role includes activin receptor activity, type II.


### Pathways affected {#pathways}

BMPR2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signaling by BMP](https://reactome.org/content/detail/R-HSA-201451) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** activin receptor activity, type II, BMP binding, cadherin binding, protein tyrosine kinase binding.

**Biological process:** osteoblast differentiation, endothelial cell proliferation, chondrocyte development, negative regulation of systemic arterial blood pressure, cell surface receptor protein serine/threonine kinase signaling pathway, cellular response to starvation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-05-03.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely Pathogenic).

**Submission history:** 4 submissions (2024–2025); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Pulmonary Hypertension VCEP (pulmonary arterial hypertension). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1`, `PM2_Supporting`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_001204.7(BMPR2):c.240_241insT (p.Lys81Ter) variant is a DNA single thymine base insertion predicted to cause a frameshift, replacing a lysine residue for a stop codon at position 81. The variant is absent from the gnomAD  v.2.1.1 controls and v3.0 (PM2_supporting). c.240_241insT was found in a patient with pulmonary arterial hypertension (PMID:20496075). The variant resides in the second exon of BMPR2 and generates a stop codon that is predicted to cause nonsense-mediated decay (PVS1). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PVS1 (VCEP specification version v 1.1, 1/18/2024).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50071 · approved 2024-05-03 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/3f6b7a5a-1054-4f88-8716-48d26795389c).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Rare Disease Genomics Group, St George's University of London | Pathogenic | no assertion criteria provided | literature only |  |
| Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2024-05-03 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-13 |

## Associated conditions {#conditions}

[pulmonary arterial hypertension](https://sugi.bio/atlas/disease/pulmonary-arterial-hypertension/), [pulmonary hypertension, primary, 1](https://sugi.bio/atlas/disease/pulmonary-hypertension-primary-1/).

**Reported phenotype names (ClinVar):** Pulmonary arterial hypertension, Pulmonary hypertension, primary, 1, Primary pulmonary hypertension, not provided, none provided, Pulmonary hypertension, familial primary, 1, with or without HHT, Idiopathic pulmonary hypertension.

## Similar variants {#similar}

Related BMPR2 variant pages (same residue, condition, or type): [BMPR2 p.Asp885fs](/variant/bmpr2-p-asp885fs), [BMPR2 p.Ile507fs](/variant/bmpr2-p-ile507fs), [BMPR2 p.Thr104fs](/variant/bmpr2-p-thr104fs), [BMPR2 p.Val429fs](/variant/bmpr2-p-val429fs), [BMPR2 c.1277-10_1277-9insGGG](/variant/bmpr2-c-1277-minus-10-1277-minus-9insggg), [BMPR2 c.852_852+1insA](/variant/bmpr2-c-852-852-plus-1insa), [BMPR2 p.Arg114fs](/variant/bmpr2-p-arg114fs), [BMPR2 p.Arg32fs](/variant/bmpr2-p-arg32fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 425725). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*