Is BMPR2 p.Cys123Arg (c.367T>C) pathogenic?

BMPR2 p.Cys123Arg (c.367T>C) is classified Pathogenic in BMPR2 (ClinVar, No assertion criteria, 4 submitters; last evaluated 2001-01-01). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Cys123Arg (c.367T>C)?

BMPR2 p.Cys123Arg (c.367T>C) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Cys123Arg (c.367T>C) in the general population?

BMPR2 p.Cys123Arg (c.367T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Cys123Arg (c.367T>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

BMPR2 p.Cys123Arg

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.367T>C · rs137852750 · VCV8808

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 2% in BMPR2
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -12.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.88 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BMPR2
Protein: p.Cys123Arg
Coding: c.367T>C
MANE Select: NM_001204
dbSNP: rs137852750
Type: single nucleotide variant
Location: chr2:202467638 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 123: a disulfide bond; a UniProt-annotated variant site (in pph1; loss of function in bmp signaling pathway; does not localize to the cell surface); 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 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.Cys123Ser 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
BMPR2 c.247+1G>A Likely 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-cys123arg (accessed [today's date]).

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