Is BMPR2 p.Arg259Cys (c.775C>T) pathogenic?

BMPR2 p.Arg259Cys (c.775C>T) is classified Uncertain significance in BMPR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.1091); Ultra-rare (popmax 0.0164%, mid); Associated with pulmonary hypertension, primary, 1.

What condition is associated with BMPR2 p.Arg259Cys (c.775C>T)?

BMPR2 p.Arg259Cys (c.775C>T) is associated with pulmonary hypertension, primary, 1, pulmonary arterial hypertension, pulmonary venoocclusive disease 1 (ClinVar).

How common is BMPR2 p.Arg259Cys (c.775C>T) in the general population?

BMPR2 p.Arg259Cys (c.775C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about BMPR2 p.Arg259Cys (c.775C>T)?

AlphaMissense predicts likely benign (score 0.1091) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg259Cys

c.775C>T · rs760996563 · VCV1339382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary hypertension, primary, 1

Computational evidence

Protein change
AlphaMissense	0.1091	likely benign
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -6.25	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	34.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00149% 24/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.005%	19,996
South Asian	0.00329%	30,362
African / African-American	0.00267%	37,446
East Asian	0.00223%	44,896
European (non-Finnish)	0.00119%	84,289

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.Arg259Cys
Coding: c.775C>T
MANE Select: NM_001204
dbSNP: rs760996563
Type: single nucleotide variant
Location: chr2:202518975 (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

pulmonary hypertension, primary, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pulmonary arterial hypertension pulmonary venoocclusive disease 1

Similar variants

BMPR2 p.Arg259His Conflicting classifications of pathogenicity ★ ⚠ 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-arg259cys (accessed [today's date]).

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