# NM_001204.7(BMPR2):c.1424C>A (p.Ser475Ter)

https://sugi.bio/variant/bmpr2-p-ser475ter

## Summary

**BMPR2 p.Ser475Ter (c.1424C>A)** is classified **Pathogenic** in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-05-03). Very rare (popmax 8.48e-05%, nfe); Associated with pulmonary arterial hypertension.

**At a glance:** Pathogenic · review: Expert panel · rsID rs1085307352 · 3 submitters · 2 linked conditions · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the BMPR2 gene that is 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.Ser475Ter |
| Coding change (HGVS c.) | c.1424C>A |
| MANE Select transcript | [NM_001204](https://www.ncbi.nlm.nih.gov/nuccore/NM_001204) |
| dbSNP | [rs1085307352](https://www.ncbi.nlm.nih.gov/snp/rs1085307352/) |
| Variant type | single nucleotide variant |
| Location | chr2:202552726-202552726 (GRCh38) |
| ClinVar | [VCV425943](https://www.ncbi.nlm.nih.gov/clinvar/variation/425943/) |

**All HGVS expressions:** `LRG_712:g.181400C>A`, `LRG_712t1:c.1424C>A`, `NC_000002.11:g.203417449C>A`, `NC_000002.12:g.202552726C>A`, `NG_009363.1:g.181400C>A`, `NM_001204.7:c.1424C>A`

## 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 7.652, GERP 2.72, 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 11 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 41.0**. 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 **8.48e-05%** (nfe) · 1/1,179,938 in the highest group · 1/1,461,756 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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 **475** lies in an α-helix; a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); the protein kinase domain; 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. p.Ser475Ter falls in the protein kinase domain.


### 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}

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

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2024); classifications have been stable.

**ClinGen expert panel:** Pathogenic — Pulmonary Hypertension VCEP (pulmonary arterial hypertension). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1`, `PM2_Supporting`, `PS4_Supporting`.
*Considered but not met:* `BS1`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The BMPR2 c.1424C>A variant is a nonsense mutation in the kinase domain (exon 11 of 13). It is predicted to result in nonsense mediated mRNA decay, and therefore meets the criteria for PVS1. It is absent from gnomAD v2.1.1 (all samples), meeting PM2_supporting. There are three reports of this variant in the literature (PMIDs 16429395, 20534176 and 32581362). However, since PMID 16429395 summarized data from multiple countries, including the UK and French populations that were the subject of the later papers, it is not possible to determine if all three probands are independent. Thus conservatively, only counted 2 probands were counted (PS4_supporting).  In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting (VCEP specification version 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/e689411a-9ea5-436f-ad52-c1b1bd9b8ae1).*
*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 |  |
| NIHR Bioresource Rare Diseases, University of Cambridge | Pathogenic | no assertion criteria provided | research |  |
| Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2024-05-03 |

## 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, Pulmonary hypertension, familial primary, 1, with or without HHT.

## 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 425943). 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.*