BMPR2 p.Glu376Ter
c.1126G>T · rs1085307301 · VCV425876
ClinGen expert panel — Pulmonary Hypertension VCEP
Pathogenic for pulmonary arterial hypertension. Applied ACMG criteria (verbatim):
PM2_supporting PVS1 PS4_Supporting
Curation rationale (ClinGen, verbatim)
BMPR2 c.1126G>T (p.Glu376Ter) variant is predicted to cause premature stop at residue 376, in exon 8, and lead to nonsense mediated decay. The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting met) and was identified in two unrelated idiopathic PAH probands (PMID: 26387786 and PMID: 31727138) (PS4_supporting met). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting (VCEP specification 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 carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | predicted | premature termination codon in exon 8 of 13 |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.5, phastCons 1 |
| Overall | ||
| CADD | 45.0 | 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
- Protein
- p.Glu376Ter
- Coding
- c.1126G>T
- MANE Select
- NM_001204
- dbSNP
- rs1085307301
- Type
- single nucleotide variant
- Location
- chr2:202530952 (GRCh38)
- Gene constraint
- LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 58.07 · 7 PDB
- Residue 376
- a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); the protein kinase domain; a UniProt-annotated variant site (in pph1; loss of localization to the plasma membrane; localized to the cytoplasm)
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 p.Glu376Lys Uncertain significance ★★★ ⚠ same residue
- 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
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-p-glu376ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown