Is BMPR2 p.Glu503Asp (c.1509A>C) pathogenic?

BMPR2 p.Glu503Asp (c.1509A>C) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 5 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.2603); Very rare (popmax 0.00446%, eas); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Glu503Asp (c.1509A>C)?

BMPR2 p.Glu503Asp (c.1509A>C) is associated with pulmonary arterial hypertension, pulmonary venoocclusive disease 1, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Glu503Asp (c.1509A>C) in the general population?

BMPR2 p.Glu503Asp (c.1509A>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BMPR2 p.Glu503Asp (c.1509A>C)?

AlphaMissense predicts likely benign (score 0.2603) — an in-silico prediction, not a clinical call.

BMPR2 p.Glu503Asp

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.1509A>C · rs1060502583 · VCV409828

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PM2

Curation rationale (ClinGen, verbatim)

The NM_001204.7(BMPR2) c.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The maximum subpopulation allele frequency in gnomAD v4.1 is 8.474e-7 (1/1180024 alleles, non-Finnish Europeans), below the PH VCEP threshold of 0.01% (PM2 met). The variant REVEL score (0.662) meets the PH VCEP threshold of >=0.644 but the AlphaMissense score (0.2603) and CADD score (17.69) are below the thresholds for pathogenicity (PP3 not met). The variant does not affect protein localization to the plasma membrane (PMID: 25688877) or cell viability (PMID: 30809644). A single luciferase assay demonstrated comparable canonical transcriptional activity to wild-type (PMID: 18321866). However, the lack of effect on canonical signaling in one assay without replication in an independent assay, did not provide conclusive evidence for non-criticality (BS3 not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2. (VCEP specifications version 2.0, 1/30/2026)

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

Computational evidence

Protein change
AlphaMissense	0.2603	likely benign
REVEL	0.662	pathogenic-leaning
SaProt	LLR -8.06	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.22, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	17.69	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

Grpmax group 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,884 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BMPR2
Protein: p.Glu503Asp
Coding: c.1509A>C
MANE Select: NM_001204
dbSNP: rs1060502583
Type: single nucleotide variant
Location: chr2:202552811 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 503: an α-helix; 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: pulmonary venoocclusive disease 1 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

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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
BMPR2 c.247+5G>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-glu503asp (accessed [today's date]).

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