# NM_001204.7(BMPR2):c.2656C>T (p.Arg886Cys)

https://sugi.bio/variant/bmpr2-p-arg886cys

## Summary

**BMPR2 p.Arg886Cys (c.2656C>T)** is classified **Likely benign** in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.2883); Rare (popmax 0.115%, afr); Associated with pulmonary arterial hypertension.

**At a glance:** Likely benign · review: Expert panel · rsID rs148770894 · 3 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.115%, afr)

## For patients & families {#patients}

This is a change in the BMPR2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 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.Arg886Cys |
| Coding change (HGVS c.) | c.2656C>T |
| MANE Select transcript | [NM_001204](https://www.ncbi.nlm.nih.gov/nuccore/NM_001204) |
| dbSNP | [rs148770894](https://www.ncbi.nlm.nih.gov/snp/rs148770894/) |
| Variant type | single nucleotide variant |
| Location | chr2:202556321-202556321 (GRCh38) |
| ClinVar | [VCV458626](https://www.ncbi.nlm.nih.gov/clinvar/variation/458626/) |

**All HGVS expressions:** `LRG_712:g.184995C>T`, `LRG_712t1:c.2656C>T`, `NC_000002.11:g.203421044C>T`, `NC_000002.12:g.202556321C>T`, `NG_009363.1:g.184995C>T`, `NM_001204.7:c.2656C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2883)
- REVEL 0.485 (indeterminate)
- SaProt LLR -7.659 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 4.9, GERP 2.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.1**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (202,552,837–202,559,733), spanning 6,896 bp. Chi-square p 0.061. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.115%** (afr) · FAF95 0.095% · FAF99 0.0878% · 86/75,048 in the highest group · 112/1,614,158 alleles overall — rare (popmax 0.115%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.115% | 873 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,501 |
| Admixed American | 0.00666% | 15,004 |
| East Asian | 0.00223% | 44,886 |
| European (non-Finnish) | 0.00127% | 78,669 |
| South Asian | 0.0011% | 91,050 |

*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 **886** 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); the 'disordered' region.

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. p.Arg886Cys falls in the disordered region.


### 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 benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-09-10.

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

**Submission history:** 3 submissions (2024–2025); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Pulmonary Hypertension VCEP (pulmonary arterial hypertension). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS1`.
*Considered but not met:* `PM2`, `PS4`, `PM1`, `PP3`, `BS2`, `BP4`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The BMPR2 c.2656C>T variant is a missense variant predicted to cause an arginine to cysteine substitution at amino acid position 886. The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.1130% (11/9738 alleles) in the African/African American population. The population evidence available meets the threshold for BS1 (≥0.1%), but not for BA1 (>5%) or PM2 (<0.01%) as defined by the ClinGen Pulmonary Hypertension VCEP (PH-VCEP). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.485 indicating that neither BP4 or PP3 were met since the threshold specified by the PH-VCEP is <0.25 and >0.75, respectively. The amino acid substitution occurs in the c-terminal domain, which is not a well-established functional domain, so PM1 was not met. Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. BS3 and PS3 were not evaluated due to the lack of functional data for this variant. In summary, the variant meets the criteria to be classified as likely benign (LB) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50071 · approved 2024-09-10 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/f559bee5-7640-4263-99c6-7feea7742bdb).*
*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 |
| --- | --- | --- | --- | --- |
| Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen | Likely Benign | reviewed by expert panel | curation | 2024-09-10 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Pulmonary arterial hypertension, Primary pulmonary hypertension, Inborn genetic diseases, Idiopathic pulmonary hypertension.

## Similar variants {#similar}

Related BMPR2 variant pages (same residue, condition, or type): [BMPR2 p.Arg886Ser](/variant/bmpr2-p-arg886ser), [BMPR2 p.Arg886His](/variant/bmpr2-p-arg886his), [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).

### 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 458626). 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.*