Is BMPR2 p.Glu386Gln (c.1156G>C) pathogenic?

BMPR2 p.Glu386Gln (c.1156G>C) is classified Likely pathogenic in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-11-06). AlphaMissense: likely pathogenic (0.9837); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Glu386Gln (c.1156G>C)?

BMPR2 p.Glu386Gln (c.1156G>C) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Glu386Gln (c.1156G>C) in the general population?

BMPR2 p.Glu386Gln (c.1156G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Glu386Gln (c.1156G>C)?

AlphaMissense predicts likely pathogenic (score 0.9837) — an in-silico prediction, not a clinical call.

BMPR2 p.Glu386Gln

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.1156G>C · rs1085307306 · VCV425884

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9837 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

Likely Pathogenic for pulmonary arterial hypertension. Applied ACMG criteria (verbatim):

PM1_Strong PM2_Supporting PM5_Supporting PP3

Curation rationale (ClinGen, verbatim)

The BMPR2 c.1156G>C variant is a missense variant predicted to cause a glutamic acid to glutamine substitution at amino acid position 386. The variant is absent from the gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Only one patient with the variant has been reported (PMID: 26387786), and therefore, PS4 is not met. Glu386Gln is located in the catalytic kinase domain and is known to be an indispensable residue (PM1_strong). Other likely pathogenic missense variants causing a different amino acid change at the same residue have been reported, including Glu386Lys, Glu386Ala, Glu386Val, and Glu386Gly (PM5_supporting). Computational evidence for pathogenicity included a REVEL score of 0.961, which meets the threshold of >0.75 defined by the ClinGen Pulmonary Hypertension VCEP, and AlphaMissense 0.9837 (PP3 met but not BP4). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence. Similarly, functional data is unavailable for this variant, so BS3 and PS3 were not evaluated. In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PM5_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.9837	likely pathogenic ✓ concordant with ClinVar · top 9% in BMPR2
REVEL	0.961	strongly pathogenic-leaning
SaProt	LLR -16.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 1,719 bp · p 3.4e-08 · regional, not allelic
Overall
CADD	32.0	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.Glu386Gln
Coding: c.1156G>C
MANE Select: NM_001204
dbSNP: rs1085307306
Type: single nucleotide variant
Location: chr2:202532612 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 386: 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); an α-helix

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: 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.Glu386Ala Likely pathogenic ★★★ same residue
BMPR2 p.Glu386Gly Likely pathogenic ★★★ same residue
BMPR2 p.Glu386Lys Likely pathogenic ★★★ same residue
BMPR2 p.Glu386Val Likely 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

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-glu386gln (accessed [today's date]).

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