# NM_004329.3(BMPR1A):c.343_345inv (p.Lys115Phe)

https://sugi.bio/variant/bmpr1a-p-lys115phe

## Summary

**BMPR1A p.Lys115Phe (c.343_345inv)** is classified **Uncertain significance** in BMPR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-26). Associated with juvenile polyposis syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the BMPR1A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to juvenile polyposis syndrome.

*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 |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 11 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BMPR1A is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Juvenile polyposis syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Juvenile colonic polyposis — Obligate (100%)
- Rectal polyposis — Obligate (100%)
- Juvenile gastrointestinal polyposis — Obligate (100%)
- Intestinal polyp — Very frequent (99-80%)
- Anemia — Frequent (79-30%)
- Abdominal pain — Frequent (79-30%)
- Hamartomatous polyposis — Frequent (79-30%)
- Small intestinal polyposis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003065/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BMPR1A](https://sugi.bio/atlas/gene/BMPR1A/) |
| Protein change (HGVS p.) | p.Lys115Phe |
| Coding change (HGVS c.) | c.343_345inv |
| MANE Select transcript | [NM_004329](https://www.ncbi.nlm.nih.gov/nuccore/NM_004329) |
| Variant type | Inversion |
| Location | chr10:86899803-86899805 (GRCh38) |
| ClinVar | [VCV1471161](https://www.ncbi.nlm.nih.gov/clinvar/variation/1471161/) |

**All HGVS expressions:** `LRG_298:g.148165_148167inv`, `NC_000010.10:g.88659560_88659562inv`, `NC_000010.11:g.86899803_86899805inv`, `NG_009362.1:g.148165_148167inv`, `NM_004329.3:c.343_345inv`

## 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 11.083, GERP 2.7, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 0.66** across the covering region of the MANE Select transcript (86,892,227–86,919,255), spanning 27,028 bp. Chi-square p 2.2e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no inversion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**BMPR1A** population constraint: LOEUF 0.195, pLI 1, missense-Z 3.9074; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **juvenile polyposis syndrome** — Definitive (AD)
- **pulmonary arterial hypertension** — Disputed (UD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.86, 54% of residues very-high.

**11 experimental structure(s)** (PDB): [1ES7](https://www.rcsb.org/structure/1ES7), [1REW](https://www.rcsb.org/structure/1REW), [2GOO](https://www.rcsb.org/structure/2GOO), [2H62](https://www.rcsb.org/structure/2H62), [2H64](https://www.rcsb.org/structure/2H64), [2K3G](https://www.rcsb.org/structure/2K3G) — incl. mutant structure 2QJ9.

## What this gene does {#gene-function}

*Describes the biological roles of BMPR1A (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:** BMPR1A's established molecular role includes protein serine/threonine kinase activity.


### Pathways affected {#pathways}

BMPR1A 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:** protein serine/threonine kinase activity, transforming growth factor beta receptor activity, type I, ATP binding, BMP binding, protein homodimerization activity, SMAD binding.

**Biological process:** angiogenesis, immune response, transforming growth factor beta receptor signaling pathway, positive regulation of gene expression, negative regulation of smooth muscle cell migration, positive regulation of bone mineralization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-03-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-26 |

## Associated conditions {#conditions}

[juvenile polyposis syndrome](https://sugi.bio/atlas/disease/juvenile-polyposis-syndrome/).

**Reported phenotype names (ClinVar):** Juvenile polyposis syndrome.

## Similar variants {#similar}

Related BMPR1A variant pages (same residue, condition, or type): [BMPR1A p.Lys115=](/variant/bmpr1a-p-lys115), [BMPR1A c.1166+1G>A](/variant/bmpr1a-c-1166-plus-1g-a), [BMPR1A c.1343-2A>G](/variant/bmpr1a-c-1343-minus-2a-g), [BMPR1A c.1473+1G>A](/variant/bmpr1a-c-1473-plus-1g-a), [BMPR1A c.1473+1G>C](/variant/bmpr1a-c-1473-plus-1g-c), [BMPR1A c.230+1G>A](/variant/bmpr1a-c-230-plus-1g-a), [BMPR1A c.333+1G>A](/variant/bmpr1a-c-333-plus-1g-a), [BMPR1A c.430+1G>A](/variant/bmpr1a-c-430-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1471161). 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.*