# NM_001204.7(BMPR2):c.1175T>C (p.Val392Ala)

https://sugi.bio/variant/bmpr2-p-val392ala

## Summary

**BMPR2 p.Val392Ala (c.1175T>C)** is classified **Uncertain significance** in BMPR2 (ClinVar, Expert panel, 2 submitters; last evaluated 2024-11-06). AlphaMissense: likely pathogenic (0.9795); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs1085307309 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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 2 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.Val392Ala |
| Coding change (HGVS c.) | c.1175T>C |
| MANE Select transcript | [NM_001204](https://www.ncbi.nlm.nih.gov/nuccore/NM_001204) |
| dbSNP | [rs1085307309](https://www.ncbi.nlm.nih.gov/snp/rs1085307309/) |
| Variant type | single nucleotide variant |
| Location | chr2:202532631-202532631 (GRCh38) |
| ClinVar | [VCV425889](https://www.ncbi.nlm.nih.gov/clinvar/variation/425889/) |

**All HGVS expressions:** `LRG_712:g.161305T>C`, `LRG_712t1:c.1175T>C`, `NC_000002.11:g.203397354T>C`, `NC_000002.12:g.202532631T>C`, `NG_009363.1:g.161305T>C`, `NM_001204.7:c.1175T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9795)
- REVEL 0.954 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.412 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.934, GERP 2.72, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in BMPR2 (of 6,099 modeled).
- CADD: **PHRED 29.0**. 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.*
- Regional missense constraint: **o/e 0.11** across the covering region of the MANE Select transcript (202,530,926–202,532,645), spanning 1,719 bp — the region is depleted of missense variation. Chi-square p 3.4e-08. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **392** lies in 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.Val392Ala 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}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-11-06.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain Significance).

**Submission history:** 2 submissions (2024); 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`, `PM1_met`, `PP3_met`.
*Considered but not met:* `PS4`, `BS2`, `BS1`, `BP4`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_001204.7(BMPR2) c.1175T>C (p.Val392Ala) variant is located in exon 9 of the BMPR2 gene and is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The variant is located in the functionally relevant catalytic kinase domain (PM1_met) but is not a critical or non-critical residue. The variant has been reported in only one individual with IPAH (PMID: 21737554 and 20002458) (PS4 not met). The REVEL score for the variant is 0.954, which is greater than the PH VCEP threshold of >= 0.75, and the AlphaMissense score is 0.9795, indicating pathogenicity (PP3_met). No segregation or parental data were found (PP1 and PS2 not evaluated). No other amino acid change at the same position has been reported for PAH (PS1 and PM5 not evaluated). No functional evidence was found (PS3 not evaluated). In summary, this variant meets the criteria to be 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: PM2_supporting, PM1, PP3 (VCEP specification version 1.1.0, 1/18/2024).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50071 · approved 2024-11-06 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/8ce94f69-5d6f-4c30-bee8-b5174220c1f0).*
*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 | Uncertain Significance | reviewed by expert panel | curation | 2024-11-06 |

## 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.

## Same-residue context {#hotspot}

Residue **392** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BMPR2 p.Val392fs](/variant/bmpr2-p-val392fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## 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 425889). 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.*