Is BMPR2 p.Glu376Lys (c.1126G>A) pathogenic?

BMPR2 p.Glu376Lys (c.1126G>A) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.9878); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Glu376Lys (c.1126G>A)?

BMPR2 p.Glu376Lys (c.1126G>A) is associated with pulmonary arterial hypertension, fibrodysplasia ossificans progressiva (ClinVar).

How common is BMPR2 p.Glu376Lys (c.1126G>A) in the general population?

BMPR2 p.Glu376Lys (c.1126G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Glu376Lys (c.1126G>A)?

AlphaMissense predicts likely pathogenic (score 0.9878) — an in-silico prediction, not a clinical call.

BMPR2 p.Glu376Lys

Q: How is Idiopathic/heritable pulmonary arterial hypertension inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1126G>A · rs1085307301 · VCV977222

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9878 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

Uncertain Significance for pulmonary arterial hypertension. Applied ACMG criteria (verbatim):

PM2_supporting PM1_met

Curation rationale (ClinGen, verbatim)

The BMPR2 c.1126G>A (p.Glu376Lys) variant is an exonic variant located 3 base pairs before the end of exon 8. The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_Supporting). The variant has not been reported in pulmonary arterial hypertension patients to date. The variant has been identified in a patient with progressive myositis ossificans and a patient with unknown phenotype (ClinVar ID 977222) (PS4_not met). The variant is located in the well-established kinase domain (PM1_met). However, protein and splice-site prediction algorithms do not predict pathogenicity ((REVEL score 0.47 (>0,25-<0.75); Splice AI score 0 (benign)) (PP3_not met, BP4_not met). PP1 was not evaluated due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for PAH (PS1, PM5 not assessed). In summary, this variant meets the criteria to be classified as VUS for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9878	likely pathogenic · top 8% in BMPR2
REVEL	0.465	indeterminate
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 1,719 bp · p 3.4e-08 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

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.Glu376Lys
Coding: c.1126G>A
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)

Full BMPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pulmonary arterial hypertension — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: fibrodysplasia ossificans progressiva

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.Glu376Ter Pathogenic ★★★ 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-glu376lys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown