Is BMPR2 p.Cys34Arg (c.100T>C) pathogenic?

BMPR2 p.Cys34Arg (c.100T>C) is classified Pathogenic in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Cys34Arg (c.100T>C)?

BMPR2 p.Cys34Arg (c.100T>C) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Cys34Arg (c.100T>C) in the general population?

BMPR2 p.Cys34Arg (c.100T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Cys34Arg (c.100T>C)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

BMPR2 p.Cys34Arg

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.100T>C · rs1085307163 · VCV425702

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

Pathogenic for pulmonary arterial hypertension. Applied ACMG criteria (verbatim):

PM1_Strong PM2_Supporting PS4_Supporting PM5_Supporting PS3 PP3

Curation rationale (ClinGen, verbatim)

The NM_001204.7(BMPR2) c.100T>C variant is a missense variant predicted to cause a cysteine to arginine substitution at amino acid position 34 (p.Cys34Arg). The variant is absent from gnomAD v.2.1.1 and v4.1 (PM2_supporting) and has been reported in two unrelated PAH probands (PMID: 29650961) (PS4_supporting). The variant is located within the extracellular ligand-binding domain and p.Cys34 is a critical residue for protein function (PM1_strong). Two additional likely pathogenic variants, c.101G>T (p.Cys34Phe) and c.102T>G (p.Cys34Trp) have been reported at the same residue (PMID: 27453251, PMID: 30578397) (PM5_supporting). HeLa cells transfected with a BMPR2 p.C34R construct demonstrated that the mutant protein is mislocalized in the cell and does not reach the plasma membrane, with some retention in the ER/Golgi (PMID: 25688877) (PS3). In silico prediction (REVEL = 0.939) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1_strong, PM2_supporting, PM5_supporting, PP3 (VCEP specification version v 1.1, 1/18/2024).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic ✓ concordant with ClinVar · top 2% in BMPR2
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -16.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	29.0	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.Cys34Arg
Coding: c.100T>C
MANE Select: NM_001204
dbSNP: rs1085307163
Type: single nucleotide variant
Location: chr2:202464832 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 34: a disulfide bond; a β-strand

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.Cys34Tyr Uncertain significance ★ ⚠ 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-cys34arg (accessed [today's date]).

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