BMPR2 c.247+2del
ClinGen expert panel — Pulmonary Hypertension VCEP
Likely Pathogenic for pulmonary arterial hypertension. Applied ACMG criteria (verbatim):
PVS1_Strong PM2_Supporting PS1_Supporting
Curation rationale (ClinGen, verbatim)
The BMPR2 c. 247+2del variant is in the canonical donor site of intron 2, leading to in frame exon skipping. The variant is absent from gnomAD v4.1.0 and v2.1.1 (controls) (PM2_supporting). This variant has been reported in one heritable PAH proband (PMID:26387786) (PS4 not met). The in frame deletion removes 5.5% of the protein, including part of the critical ligand binding domain (PVS1_strong). RNA data showed two transcripts, one deleting amino acids 47-82 and one deleting aa63-82, both removing critical cysteine residues (Cys60 and Cys66) (PMID:26387786). SpliceAI (0.95) is consistent with a detrimental effect on splicing. Another variant in the same splice region, c.247+1, was classified as likely pathogenic by the PH VCEP (PS1_supporting). PP1, PS2, and PM6 were not assessed due to absence of co-segregation data. In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong(RNA), PS1_supporting, PM2_supporting (VCEP specification version 2.0, 1/30/2026)
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 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 | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.7, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- BMPR2
- Coding
- c.247+2del
- MANE Select
- NM_001204
- dbSNP
- rs1085307190
- Type
- Deletion
- Location
- chr2:202464981 (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.247+1_247+7del Likely pathogenic ★★★ same condition
- BMPR2 c.419-38del Benign ★★★ same condition
- BMPR2 p.Asn861fs Pathogenic ★★ same condition
- BMPR2 p.Gly390fs Pathogenic/Likely pathogenic ★★ same condition
- BMPR2 p.Lys230fs Pathogenic ★★ same condition
- BMPR2 p.Phe773fs Pathogenic ★★ same condition
- BMPR2 p.Pro366fs Pathogenic ★★ same condition
- BMPR2 p.Pro739fs 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-247-plus-2del (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown