# NM_004329.3(BMPR1A):c.183C>T (p.Cys61=)

https://sugi.bio/variant/bmpr1a-p-cys61

## Summary

**BMPR1A p.Cys61= (c.183C>T)** is classified **Conflicting classifications of pathogenicity** in BMPR1A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-10-27). Ultra-rare (popmax 0.0164%, mid); Associated with juvenile polyposis syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs140610221 · 9 submitters · 2 linked conditions · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the BMPR1A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, 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.Cys61= |
| Coding change (HGVS c.) | c.183C>T |
| MANE Select transcript | [NM_004329](https://www.ncbi.nlm.nih.gov/nuccore/NM_004329) |
| dbSNP | [rs140610221](https://www.ncbi.nlm.nih.gov/snp/rs140610221/) |
| Variant type | single nucleotide variant |
| Location | chr10:86890177-86890177 (GRCh38) |
| ClinVar | [VCV482845](https://www.ncbi.nlm.nih.gov/clinvar/variation/482845/) |

**All HGVS expressions:** `LRG_298:g.138539C>T`, `LRG_298t1:c.183C>T`, `NC_000010.10:g.88649934C>T`, `NC_000010.11:g.86890177C>T`, `NG_009362.1:g.138539C>T`, `NM_004329.3:c.183C>T`

## 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 1.793, GERP 0.165, phastCons 1 — weakly conserved position
- CADD: **PHRED 11.38**. 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 **0.0164%** (mid) · FAF95 0.00138% · FAF99 0.00116% · 1/6,084 in the highest group · 29/1,613,994 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| African / African-American | 0.004% | 24,972 |
| European (non-Finnish) | 0.00203% | 49,168 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |

*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}

Residue **61** lies in a disulfide bond; a β-strand.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-27.

**Submitter consensus:** conflicting (6 Likely benign, 1 Likely Benign, 1 Benign, 1 Uncertain significance).

**Submission history:** 9 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-07-24 |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-04-10 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2017-05-07 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-18 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-03-02 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-07-31 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-27 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Juvenile polyposis syndrome, Hereditary cancer-predisposing syndrome, not provided, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome, none provided.

## Similar variants {#similar}

Related BMPR1A variant pages (same residue, condition, or type): [BMPR1A p.Cys61Tyr](/variant/bmpr1a-p-cys61tyr), [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 2026-10-06); 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 2026-10-14); 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 482845). 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.*