Is BMPR2 p.Cys99Arg (c.295T>C) pathogenic?

BMPR2 p.Cys99Arg (c.295T>C) is classified Conflicting classifications of pathogenicity in BMPR2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 8.75e-05%, nfe); Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Cys99Arg (c.295T>C)?

BMPR2 p.Cys99Arg (c.295T>C) is associated with Primary pulmonary hypertension, pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Cys99Arg (c.295T>C) in the general population?

BMPR2 p.Cys99Arg (c.295T>C) is very rare (popmax 8.75e-05%, nfe) (gnomAD).

What do computational predictors say about BMPR2 p.Cys99Arg (c.295T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

BMPR2 p.Cys99Arg

c.295T>C · rs863223425 · VCV212816

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.75e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 1% in BMPR2
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -13.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	29.5	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 8.75e-05% European (non-Finnish) · 1/1,142,474 alleles

Overall 0.000657% 1/152,168 alleles · very rare

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.Cys99Arg
Coding: c.295T>C
MANE Select: NM_001204
dbSNP: rs863223425
Type: single nucleotide variant
Location: chr2:202467566 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 99: a disulfide bond

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 arterial hypertension pulmonary hypertension, primary, 1

Similar variants

BMPR2 p.Cys99Tyr Pathogenic ★ same residue
BMPR2 p.Cys99Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
BMPR2 p.Cys99Phe 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

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-cys99arg (accessed [today's date]).

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