# NM_001204.7(BMPR2):c.136A>G (p.Ile46Val)

https://sugi.bio/variant/bmpr2-p-ile46val

## Summary

**BMPR2 p.Ile46Val (c.136A>G)** is classified **Uncertain significance** in BMPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-15). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.004%, afr); Associated with pulmonary hypertension, primary, 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs759804753 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.004%, afr)

## 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 hypertension, primary, 1.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025415/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.Ile46Val |
| Coding change (HGVS c.) | c.136A>G |
| MANE Select transcript | [NM_001204](https://www.ncbi.nlm.nih.gov/nuccore/NM_001204) |
| dbSNP | [rs759804753](https://www.ncbi.nlm.nih.gov/snp/rs759804753/) |
| Variant type | single nucleotide variant |
| Location | chr2:202464868-202464868 (GRCh38) |
| ClinVar | [VCV195138](https://www.ncbi.nlm.nih.gov/clinvar/variation/195138/) |

**All HGVS expressions:** `LRG_712:g.93542A>G`, `NC_000002.11:g.203329591A>G`, `NC_000002.12:g.202464868A>G`, `NG_009363.1:g.93542A>G`, `NM_001204.7:c.136A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0765)
- REVEL 0.317 (indeterminate)
- SaProt LLR -6.07 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.91) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.37, GERP 1.71, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.8**. 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 0.78** across the covering region of the MANE Select transcript (202,377,475–202,530,925), spanning 153,450 bp. Chi-square p 2.6e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.65**, acceptor gain **0.00**, donor gain **0.91**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.91**.
- Pangolin: Δ**0.80** (gain), gain 0.80 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,916 in the highest group · 3/1,613,998 alleles overall — very rare (popmax 0.004%, afr).

*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 **46** lies in a disulfide bond; a turn.

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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-11-15.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2015–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-05-19 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Pulmonary hypertension, primary, 1, not provided, Pulmonary venoocclusive disease 1, none provided, Pulmonary hypertension, familial primary, 1, with or without HHT, Pulmonary venoocclusive disease 1, autosomal dominant.

## Similar variants {#similar}

Related BMPR2 variant pages (same residue, condition, or type): [BMPR2 p.Ile46Thr](/variant/bmpr2-p-ile46thr), [BMPR2 p.Ile46Leu](/variant/bmpr2-p-ile46leu), [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 195138). 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.*