Is BMPR2 p.Arg491Trp (c.1471C>T) pathogenic?

BMPR2 p.Arg491Trp (c.1471C>T) is classified Pathogenic in BMPR2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9967); Absent from gnomAD v4.1; Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Arg491Trp (c.1471C>T)?

BMPR2 p.Arg491Trp (c.1471C>T) is associated with Primary pulmonary hypertension, pulmonary arterial hypertension, pulmonary venoocclusive disease 1 (ClinVar).

How common is BMPR2 p.Arg491Trp (c.1471C>T) in the general population?

BMPR2 p.Arg491Trp (c.1471C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Arg491Trp (c.1471C>T)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg491Trp

c.1471C>T · rs137852746 · VCV8802

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic ✓ concordant with ClinVar · top 4% in BMPR2
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -15.89	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 1.3	GERP 1.1, phastCons 0.97
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	31.0	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.Arg491Trp
Coding: c.1471C>T
MANE Select: NM_001204
dbSNP: rs137852746
Type: single nucleotide variant
Location: chr2:202552773 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 491: a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); the protein kinase domain; a UniProt-annotated variant site (in pph1; loss of localization to the plasma membrane; localized to the cytoplasm); a UniProt-annotated variant site (in pph1; pathogenic; no effect on localization to the cell surface); a UniProt-annotated variant site (in pph1; loss of function in bmp signaling pathway via smad proteins activation; no effect on localization to the cell surface; no effect on bmp4 binding; when transfected in epithelial cells it results in constitutive p38mapk phosphorylation consistent with a gain of function in the activation of p38mapk cascade)

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 venoocclusive disease 1 pulmonary hypertension, primary, 1

Similar variants

BMPR2 p.Arg491Gln Pathogenic ★★★ same residue
BMPR2 p.Arg491Leu 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-arg491trp (accessed [today's date]).

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