Is BMPR2 p.Gly47Asp (c.140G>A) pathogenic?

BMPR2 p.Gly47Asp (c.140G>A) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 2 submitters; last evaluated 2025-01-22). AlphaMissense: likely benign (0.1242); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Gly47Asp (c.140G>A)?

BMPR2 p.Gly47Asp (c.140G>A) is associated with pulmonary arterial hypertension (ClinVar).

How common is BMPR2 p.Gly47Asp (c.140G>A) in the general population?

BMPR2 p.Gly47Asp (c.140G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Gly47Asp (c.140G>A)?

AlphaMissense predicts likely benign (score 0.1242) — an in-silico prediction, not a clinical call.

BMPR2 p.Gly47Asp

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.140G>A · rs1085307168 · VCV425707

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1242 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 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_moderate

Curation rationale (ClinGen, verbatim)

The NM_001204.7(BMPR2):c.140G>A (p.Gly47Asp) variant is a missense variant located within exon 2 of BMPR2, predicted to cause substitution of glycine to an aspartic acid. This variant is located within the conserved extracellular domain of the protein but does not affect a known critical residue (PM1_moderate). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.55, which is below our threshold of >=0.75 for pathogenicity (PP3_not met) and above our threshold for benignity (BP4 not met). The variant has been reported in an individual with PAH associated with congenital heart disease (PMID: 15358693) but not in patients with hereditary or idiopathic PAH (PS4 not met). Alternative alleles at the same nucleotide or amino acid have not been reported (PS1 and PM5 not met). Functional studies have not been reported (PS3, not evaluated). Neither segregation or maternity/paternity studies have not been reported (PS2, PP1, BS4 not evaluated). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, 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	0.1242	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -3.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.73	donor loss · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Gly47Asp
Coding: c.140G>A
MANE Select: NM_001204
dbSNP: rs1085307168
Type: single nucleotide variant
Location: chr2:202464872 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 47: a disulfide bond; a turn

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

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.Gly47Arg 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-gly47asp (accessed [today's date]).

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