Is BMPR2 p.Arg491fs (c.1468_1469dup) pathogenic?

BMPR2 p.Arg491fs (c.14681469dup) is classified Pathogenic in BMPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-15). Associated with BMPR2-related disorder.

What condition is associated with BMPR2 p.Arg491fs (c.1468_1469dup)?

BMPR2 p.Arg491fs (c.1468_1469dup) is associated with BMPR2-related disorder (ClinVar).

BMPR2 p.Arg491fs

c.1468_1469dup · VCV4959454

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

BMPR2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3	GERP -0.21, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: BMPR2
Protein: p.Arg491fs
Coding: c.1468_1469dup
MANE Select: NM_001204
Type: Duplication
Location: chr2:202552769 (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

BMPR2-related disorder

Similar variants

BMPR2 p.Arg491Gln Pathogenic ★★★ same residue
BMPR2 p.Arg491Trp Pathogenic ★★ same residue
BMPR2 p.Arg491Leu Pathogenic ★ same residue
BMPR2 p.Leu198fs Likely pathogenic ★ same condition
BMPR2 p.Leu577fs Likely pathogenic ★ same condition
BMPR2 p.Arg321Ter Pathogenic ★★ same condition
BMPR2 p.Arg332Ter Pathogenic ★★ same condition
BMPR2 p.Arg591Ter Pathogenic/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-arg491fs (accessed [today's date]).

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