Is BMPR2 p.Arg303His (c.908G>A) pathogenic?

BMPR2 p.Arg303His (c.908G>A) is classified Likely pathogenic in BMPR2 (ClinVar, Expert panel, 6 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1054); Ultra-rare (popmax 0.0165%, mid); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Arg303His (c.908G>A)?

BMPR2 p.Arg303His (c.908G>A) is associated with pulmonary arterial hypertension, pulmonary venoocclusive disease 1, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Arg303His (c.908G>A) in the general population?

BMPR2 p.Arg303His (c.908G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BMPR2 p.Arg303His (c.908G>A)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg303His

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.908G>A · rs200948870 · VCV425842

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PS3 PM1

Curation rationale (ClinGen, verbatim)

The BMPR2 c.908G>A variant is a missense variant in exon 7 predicted to result in substitution of arginine to histidine at amino acid position 303 (p. Arg303His). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.00043 (1/2334 alleles) in subpopulation “remaining individuals” which exceeds the ClinGen PH VCEP threshold (<0.01%) for PM2 (PM2 not met). Neither BS1 (≥0.1%) nor BA1 (1%) met. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. The variant is located in the kinase domain (PM1 met). Genetic evidence showed the presence of the variant in only one IPAH patient (PMID:16429395) (PS4 not met). Immunofluorescence staining of Hela cells transfected with an R303H mutant construct showed mislocalization of BMPR2 protein to the endoplasmic reticulum (PMID:25688877) and included positive and negative controls (PS3 met). In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PM1 (VCEP specification version 1.1, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign ⚠ discordant with ClinVar
REVEL	0.497	indeterminate
SaProt	LLR -9.39	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 2.4, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.00409% 66/1,612,518 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
South Asian	0.00989%	10,116
Admixed American	0.00837%	11,954
African / African-American	0.00671%	14,900
European (non-Finnish)	0.00364%	27,438
Remaining individualsnot grpmax-eligible	0.0032%	31,241
East Asian	0.00223%	44,818

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.Arg303His
Coding: c.908G>A
MANE Select: NM_001204
dbSNP: rs200948870
Type: single nucleotide variant
Location: chr2:202520142 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 303: 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 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

BMPR2 p.Arg303Cys Uncertain significance ★ ⚠ same residue
BMPR2 p.Arg303Gly Uncertain significance ★ same residue
BMPR2 p.Arg303= Likely benign ★ 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

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-arg303his (accessed [today's date]).

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