# NM_001204.7(BMPR2):c.2352C>T (p.Val784=)

https://sugi.bio/variant/bmpr2-p-val784

## Summary

**BMPR2 p.Val784= (c.2352C>T)** is classified **Uncertain significance** in BMPR2 (ClinVar, Expert panel, 4 submitters; last evaluated 2026-04-10). Very rare (popmax 0.00602%, nfe); Associated with pulmonary arterial hypertension.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs767560978 · 4 submitters · 2 linked conditions · very rare (popmax 0.00602%, nfe)

## For patients & families {#patients}

This is a change in the BMPR2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Val784= |
| Coding change (HGVS c.) | c.2352C>T |
| MANE Select transcript | [NM_001204](https://www.ncbi.nlm.nih.gov/nuccore/NM_001204) |
| dbSNP | [rs767560978](https://www.ncbi.nlm.nih.gov/snp/rs767560978/) |
| Variant type | single nucleotide variant |
| Location | chr2:202556017-202556017 (GRCh38) |
| ClinVar | [VCV333647](https://www.ncbi.nlm.nih.gov/clinvar/variation/333647/) |

**All HGVS expressions:** `LRG_712:g.184691C>T`, `LRG_712t1:c.2352C>T`, `NC_000002.11:g.203420740C>T`, `NC_000002.12:g.202556017C>T`, `NG_009363.1:g.184691C>T`, `NM_001204.7:c.2352C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.437, GERP 0.023, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 6.953**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00602%** (nfe) · FAF95 0.00486% · FAF99 0.00447% · 71/1,180,018 in the highest group · 77/1,614,008 alleles overall — very rare (popmax 0.00602%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00602% | 16,620 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,014 |
| African / African-American | 0.00133% | 74,908 |
| South Asian | 0.0011% | 91,082 |

*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 **784** lies in a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); a UniProt-annotated variant site (in pph1; loss of localization to the plasma membrane; localized to the cytoplasm).

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}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-04-10.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 4 submissions (2018–2026); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — Pulmonary Hypertension VCEP (pulmonary arterial hypertension). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `BP7`, `BP4`.
*Considered but not met:* `PS4`, `PM1`, `BS1`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_001204.7(BMPR2) c.2352C>T variant is a synonymous (silent) variant (p.Val784=). This variant is present in gnomADv2.1.1 controls at a frequency of 0.00002 and gnomADv4.1 at 0.00006 (PM2_supporting). In silico prediction algorithms indicate that the nucleotide is not highly conserved (REVEL score not available; CADD = 1.4; phyloP = 0.207) (BP4) and has no impact on splicing (SpliceAI = 0) (BP7). In summary, this variant is classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BP4, BP7, PM2_supporting. (VCEP specifications version 2.0, 1/30/2026)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50071 · approved 2026-04-10 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/56885255-cd86-4c5d-887f-dfd7f2b7ad29).*
*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 |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-12-24 |
| Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen | Uncertain Significance | reviewed by expert panel | curation | 2026-04-10 |

## 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, Inborn genetic diseases, 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 c.1276+3A>G](/variant/bmpr2-c-1276-plus-3a-g), [BMPR2 c.1276+3A>T](/variant/bmpr2-c-1276-plus-3a-t), [BMPR2 c.1276+4A>G](/variant/bmpr2-c-1276-plus-4a-g), [BMPR2 c.1277-8A>G](/variant/bmpr2-c-1277-minus-8a-g), [BMPR2 c.1277-9A>G](/variant/bmpr2-c-1277-minus-9a-g), [BMPR2 c.1413+1G>A](/variant/bmpr2-c-1413-plus-1g-a), [BMPR2 c.247+1G>A](/variant/bmpr2-c-247-plus-1g-a), [BMPR2 c.247+5G>A](/variant/bmpr2-c-247-plus-5g-a).

### 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 333647). 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.*