Is BMPR2 p.Arg842Ser (c.2526G>T) pathogenic?

BMPR2 p.Arg842Ser (c.2526G>T) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.2971); Very rare (popmax 0.00416%, nfe); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Arg842Ser (c.2526G>T)?

BMPR2 p.Arg842Ser (c.2526G>T) is associated with pulmonary arterial hypertension, pulmonary venoocclusive disease 1, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Arg842Ser (c.2526G>T) in the general population?

BMPR2 p.Arg842Ser (c.2526G>T) is very rare (popmax 0.00416%, nfe) (gnomAD).

What do computational predictors say about BMPR2 p.Arg842Ser (c.2526G>T)?

AlphaMissense predicts likely benign (score 0.2971) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg842Ser

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.2526G>T · rs368819325 · VCV1398400

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00416%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The BMPR2 c.1882A>G variant is a missense variant predicted to result in an arginine to serine substitution at amino acid position 842 (p.Arg842Ser). The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.000070 in the European (non-Finnish) population thus meeting the threshold for PM2_supporting, resultantly neither BS1 nor BA1 were met. Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.468 indicating that neither BP4 nor PP3 were met. Additionally, the SpliceAI algorithm predicts no deleterious impact on putative acceptor or donor splice sites. The BMPR2 C-terminus is of unclear functional and/or structural relevance, hence PM1 is not met. Due to no evidence of familial segregation PP1, PM6 and PS2 were not assessed. BS3 and PS3 were not evaluated as functional data is unavailable for this variant. In summary, the variant meets the criteria to be classified as a variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting (VCEP specification version 1.1, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.2971	likely benign
REVEL	0.468	indeterminate
SaProt	LLR -4.97	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 1.4	GERP -1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 6,896 bp · p 0.061 · regional, not allelic
Overall
CADD	15.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00416% European (non-Finnish) · 49/1,177,884 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00317% 51/1,611,346 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00416%	24,038
Remaining individualsnot grpmax-eligible	0.00321%	31,187

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.Arg842Ser
Coding: c.2526G>T
MANE Select: NM_001204
dbSNP: rs368819325
Type: single nucleotide variant
Location: chr2:202556191 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 842: a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); a UniProt-annotated variant site (in pph1; loss of localization to the plasma membrane; localized to the cytoplasm)

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 venoocclusive disease 1 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.Arg842fs Pathogenic same residue
BMPR2 p.Arg842Lys Uncertain significance ★ ⚠ same residue
BMPR2 p.Arg842= Likely benign ★ 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-arg842ser (accessed [today's date]).

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