BMPR2 c.529+2T>C
ClinGen expert panel — Pulmonary Hypertension VCEP
Uncertain Significance for pulmonary arterial hypertension. Applied ACMG criteria (verbatim):
PVS1_Strong PM2_Supporting
Curation rationale (ClinGen, verbatim)
The NM_001204.7(BMPR2) c.529+2T>C variant is located in the canonical donor splice site of intron 4. It is predicted to cause skipping of biologically relevant exon 4 (111 bp), resulting in an in-frame deletion of amino acids Ser140-Thr176 within the transmembrane domain, that is predicted to escape nonsense-mediated decay (PVS1_strong). The predictions were recorded under PVS1, so PP3 was not applied to avoid double counting. Although the variant is predicted to cause a change in the length of the protein due to in-frame deletion, no functional data are available and thus PM4 was not applied. This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Consequence | canonical splice-site (±1/±2) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| Splicing | ||
| Splice region | donor +2 | canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone |
| SpliceAI | Δ0.97 | donor loss · deltas |
| Pangolin | Δ0.85 | loss · gain 0.01 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 2.5, phastCons 1 |
| Non-coding constraint | Z 1.89 | 1 kb window · o/e 0.85 · regional · uncalibrated |
| Overall | ||
| CADD | 27.9 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- BMPR2
- Coding
- c.529+2T>C
- MANE Select
- NM_001204
- dbSNP
- rs1085307241
- Type
- single nucleotide variant
- Location
- chr2:202513831 (GRCh38)
- Gene constraint
- LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 58.07 · 7 PDB
Disease context
pulmonary arterial hypertension — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: pulmonary hypertension, primary, 1
For Idiopathic/heritable pulmonary arterial hypertension (Orphanet):
- Inheritance
- Autosomal dominant, Autosomal recessive, Not applicable
- Onset
- All ages
- Prevalence
- 1-9 / 1 000 000 (United States)
Similar variants
- BMPR2 c.1276+3A>G Likely pathogenic ★★★ same condition
- BMPR2 c.1276+3A>T Likely pathogenic ★★★ same condition
- BMPR2 c.1276+4A>G Likely pathogenic ★★★ same condition
- BMPR2 c.1277-8A>G Pathogenic ★★★ same condition
- BMPR2 c.1277-9A>G Pathogenic ★★★ same condition
- BMPR2 c.1413+1G>A Pathogenic ★★★ same condition
- BMPR2 c.247+1G>A Likely pathogenic ★★★ same condition
- BMPR2 c.247+5G>A Likely pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/bmpr2-c-529-plus-2t-c (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown