Is BMPR2 p.Cys420Phe (c.1259G>T) pathogenic?

BMPR2 p.Cys420Phe (c.1259G>T) is classified Likely pathogenic in BMPR2 (ClinVar, Expert panel, 1 submitter; last evaluated 2026-04-10). AlphaMissense: likely pathogenic (0.9727); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Cys420Phe (c.1259G>T)?

BMPR2 p.Cys420Phe (c.1259G>T) is associated with pulmonary arterial hypertension (ClinVar).

How common is BMPR2 p.Cys420Phe (c.1259G>T) in the general population?

BMPR2 p.Cys420Phe (c.1259G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Cys420Phe (c.1259G>T)?

AlphaMissense predicts likely pathogenic (score 0.9727) — an in-silico prediction, not a clinical call.

BMPR2 p.Cys420Phe

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.1259G>T · VCV3899317

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9727 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PM2_Supporting PS4_Supporting PM1_moderate PP3_supporting PM5_moderate

Curation rationale (ClinGen, verbatim)

BMPR2 c.1259G>T is a missense variant predicted to cause substitution of cysteine to phenylalanine at amino acid position 420 (p.Cys420Phe). The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). A REVEL score of 0.914 meets PP3_supporting (>0.75). The variant resides in the conserved catalytic kinase domain but does not affect a known critical residue (PM1_moderate). The variant has been reported in two unrelated PAH probands, one heritable (PMID: 27453251) and one idiopathic (PMID: 30578397, 32634488) (PS4_supporting). A different missense variant at the same amino acid residue, p.Cys420Arg (PMID: 11115378, 21801371) was classified by the PH VCEP as pathogenic (PM5_moderate). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM5_moderate, PS4_supporting, PM2_supporting, PP3_supporting (VCEP specification version 2.0, 1/30/2026).

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

Computational evidence

Protein change
AlphaMissense	0.9727	likely pathogenic ✓ concordant with ClinVar
REVEL	0.914	moderately pathogenic-leaning
SaProt	LLR -14.35	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 2.4, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	33.0	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.Cys420Phe
Coding: c.1259G>T
MANE Select: NM_001204
Type: single nucleotide variant
Location: chr2:202532715 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 420: 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; loss of function in bmp signaling pathway; does not localize to the cell surface)

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

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.Cys420Arg Pathogenic ★★★ same residue
BMPR2 p.Cys420Tyr Likely pathogenic ★★★ same residue
BMPR2 p.Cys420= 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-cys420phe (accessed [today's date]).

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