Is BMPR2 p.Tyr589Cys (c.1766A>G) pathogenic?

BMPR2 p.Tyr589Cys (c.1766A>G) is classified Likely benign in BMPR2 (ClinVar, Expert panel, 6 submitters; last evaluated 2024-05-03). AlphaMissense: likely benign (0.2633); Ultra-rare (popmax 0.035%, amr); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Tyr589Cys (c.1766A>G)?

BMPR2 p.Tyr589Cys (c.1766A>G) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Tyr589Cys (c.1766A>G) in the general population?

BMPR2 p.Tyr589Cys (c.1766A>G) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about BMPR2 p.Tyr589Cys (c.1766A>G)?

AlphaMissense predicts likely benign (score 0.2633) — an in-silico prediction, not a clinical call.

BMPR2 p.Tyr589Cys

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.1766A>G · rs199915496 · VCV425966

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2633 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

BS1

Curation rationale (ClinGen, verbatim)

The BMPR2 c.1766A>G variant is a missense variant predicted to result in a tyrosine to cysteine substitution at amino acid 589 (p.Tyr589Cys). The minor allele frequency in gnomAD v2.1.1 controls at a frequency of 0.001511 (22/14,556 alleles) which is above the cut-off of 0.1% for PAH (BS1 met). The variant is located outside of the critical extracellular and kinase domains of BMPR2 (PM1 not met). The REVEL score is 0.577, not exceeding the threshold of >=0.75 (PP3 not met) or <=0.25 (BP4 not met). No functional data was available and SpliceAI does not predict an effect on splicing. In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.2633	likely benign
REVEL	0.577	indeterminate
SaProt	LLR -6.99	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 6,896 bp · p 0.061 · regional, not allelic
Overall
CADD	28.0	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

Grpmax group 0.035% Admixed American · 21/60,020 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0118% 190/1,614,222 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0874%	1,144
Admixed Americangrpmax	0.035%	2,858
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Middle Eastern	0.0165%	6,062
South Asian	0.00769%	13,012
European (non-Finnish)	0.00729%	13,721
East Asian	0.00223%	44,894
African / African-American	0.00133%	75,058

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr589Cys
Coding: c.1766A>G
MANE Select: NM_001204
dbSNP: rs199915496
Type: single nucleotide variant
Location: chr2:202555431 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 589: 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 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.Tyr589= 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
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-tyr589cys (accessed [today's date]).

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