Is BMPR2 p.Cys496Tyr (c.1487G>A) pathogenic?

BMPR2 p.Cys496Tyr (c.1487G>A) is classified Pathogenic/Likely pathogenic in BMPR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-13). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Cys496Tyr (c.1487G>A)?

BMPR2 p.Cys496Tyr (c.1487G>A) is associated with Primary pulmonary hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Cys496Tyr (c.1487G>A) in the general population?

BMPR2 p.Cys496Tyr (c.1487G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Cys496Tyr (c.1487G>A)?

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

BMPR2 p.Cys496Tyr

c.1487G>A · rs1085307362 · VCV425954

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

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

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic ✓ concordant with ClinVar · top 2% in BMPR2
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -14.69	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 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-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.Cys496Tyr
Coding: c.1487G>A
MANE Select: NM_001204
dbSNP: rs1085307362
Type: single nucleotide variant
Location: chr2:202552789 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 496: an α-helix; 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)

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 hypertension, primary, 1

Similar variants

BMPR2 p.Cys496Trp Likely pathogenic ★ same residue
BMPR2 p.Cys496Arg 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-cys496tyr (accessed [today's date]).

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