Is BMPR2 p.Arg873Gln (c.2618G>A) pathogenic?

BMPR2 p.Arg873Gln (c.2618G>A) is classified Benign in BMPR2 (ClinVar, Expert panel, 4 submitters; last evaluated 2026-04-10). AlphaMissense: likely benign (0.2661); Ultra-rare (popmax 0.0557%, eas); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Arg873Gln (c.2618G>A)?

BMPR2 p.Arg873Gln (c.2618G>A) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Arg873Gln (c.2618G>A) in the general population?

BMPR2 p.Arg873Gln (c.2618G>A) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

What do computational predictors say about BMPR2 p.Arg873Gln (c.2618G>A)?

AlphaMissense predicts likely benign (score 0.2661) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg873Gln

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.2618G>A · rs201781338 · VCV425999

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2661 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

BS1 BS4 BS3_Supporting

Curation rationale (ClinGen, verbatim)

The c.2618G>A variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 873 (p.Arg873Gln). The highest population minor allele frequency in gnomAD v2.2.1 controls is 0.001595 in Other East Asian, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold (≥0.001) for BS1 but great than the threshold for BA1 (>05%) (BS1 met). This variant was reported to not segregate with pulmonary arterial hypertension in one affected family member from one family (BS4; Internal PH VCEP member contribution). In vitro reporter system assay in mouse embryonic endothelial cells showed that the c.2618 G>A variant activated BRE-Luc (specific reporter gene for Smad1/5 activation) in response to BMP4 treatment in a similar way as the wild-type BMPR2 reporter gene. However the impairment of another function through an alternative signaling pathway of BMPRII could not be excluded (PMID 25429696)(BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 2.0, 1/30/2026): BS4, BS1, BS3_Supporting.

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

Computational evidence

Protein change
AlphaMissense	0.2661	likely benign
REVEL	0.551	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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 0.92	unconstrained · MANE · 6,896 bp · p 0.061 · regional, not allelic
Overall
CADD	26.0	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

Grpmax group 0.0557% East Asian · 25/44,880 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00564% 91/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,795
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.00475%	21,072
African / African-American	0.004%	25,019
South Asian	0.00329%	30,353

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.Arg873Gln
Coding: c.2618G>A
MANE Select: NM_001204
dbSNP: rs201781338
Type: single nucleotide variant
Location: chr2:202556283 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 873: a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); a UniProt-annotated variant site (in pph1; loss of localization to the plasma membrane; localized to the cytoplasm); the 'disordered' region

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.Arg873Ter Pathogenic/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
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-arg873gln (accessed [today's date]).

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