Is BMPR2 p.Arg259His (c.776G>A) pathogenic?

BMPR2 p.Arg259His (c.776G>A) is classified Conflicting classifications of pathogenicity in BMPR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-12). AlphaMissense: likely benign (0.0634); Ultra-rare (popmax 0.0967%, amr); Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Arg259His (c.776G>A)?

BMPR2 p.Arg259His (c.776G>A) is associated with Primary pulmonary hypertension, pulmonary venoocclusive disease 1, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Arg259His (c.776G>A) in the general population?

BMPR2 p.Arg259His (c.776G>A) is ultra-rare (popmax 0.0967%, amr) (gnomAD).

What do computational predictors say about BMPR2 p.Arg259His (c.776G>A)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg259His

c.776G>A · rs200960921 · VCV2720468

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0967%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -5.35	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 4.5	GERP -0.047, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	23.2	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 0.0967% Admixed American · 58/59,984 alleles

Filtering AF 0.0768% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0696%

Overall 0.00471% 76/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0967%	1,034
East Asian	0.00668%	14,965
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00134%	74,890
South Asian	0.0011%	91,088
European (non-Finnish)	0.00102%	98,337

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.Arg259His
Coding: c.776G>A
MANE Select: NM_001204
dbSNP: rs200960921
Type: single nucleotide variant
Location: chr2:202518976 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 259: a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); the protein kinase domain

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 venoocclusive disease 1 pulmonary hypertension, primary, 1

Similar variants

BMPR2 p.Arg259Cys Uncertain significance ★ ⚠ same residue
BMPR2 p.Arg259fs 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

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-arg259his (accessed [today's date]).

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