Is BMPR2 p.Arg225His (c.674G>A) pathogenic?

BMPR2 p.Arg225His (c.674G>A) is classified Benign/Likely benign in BMPR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0857); Ultra-rare (popmax 0.02%, amr); Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Arg225His (c.674G>A)?

BMPR2 p.Arg225His (c.674G>A) is associated with Primary pulmonary hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Arg225His (c.674G>A) in the general population?

BMPR2 p.Arg225His (c.674G>A) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about BMPR2 p.Arg225His (c.674G>A)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg225His

c.674G>A · rs148682262 · VCV333640

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	29.3	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 0.02% Admixed American · 12/60,008 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.0211% 340/1,614,174 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.696%	144
Remaining individualsnot grpmax-eligible	0.072%	1,389
Admixed Americangrpmax	0.02%	5,001
European (non-Finnish)	0.0061%	16,389
South Asian	0.00439%	22,770
African / African-American	0.00133%	75,032

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg225His
Coding: c.674G>A
MANE Select: NM_001204
dbSNP: rs148682262
Type: single nucleotide variant
Location: chr2:202518874 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 225: a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); the protein kinase domain; a β-strand

Full BMPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Primary pulmonary hypertension — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pulmonary hypertension, primary, 1

Similar variants

BMPR2 p.Arg225Cys Uncertain significance ★★ ⚠ same residue
BMPR2 p.Arg225fs Pathogenic same residue
BMPR2 p.Arg225= 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-arg225his (accessed [today's date]).

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