Is BMPR2 p.Cys420Arg (c.1258T>C) pathogenic?

BMPR2 p.Cys420Arg (c.1258T>C) is classified Pathogenic in BMPR2 (ClinVar, Expert panel, 2 submitters; last evaluated 2025-01-22). AlphaMissense: likely pathogenic (0.9969); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Cys420Arg (c.1258T>C)?

BMPR2 p.Cys420Arg (c.1258T>C) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Cys420Arg (c.1258T>C) in the general population?

BMPR2 p.Cys420Arg (c.1258T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Cys420Arg (c.1258T>C)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

BMPR2 p.Cys420Arg

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.1258T>C · rs1085307324 · VCV425906

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9969 · 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

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

PM2_Supporting PS3_strong PS4_strong PM1_Supporting PP3_suporting

Curation rationale (ClinGen, verbatim)

BMPR2 c.1258T>C is a missense variant predicted to cause substitution of cysteine to arginine at amino acid position 420 (p.Cys420Arg). This variant resides within the catalytic kinase domain but is not a known critical residue (PM1_moderate met). The variant is absent in gnomAD databases, meeting PM2_supporting criterion (BA1 and BS1 not met). The REVEL score of 0.934 meets PP3_suporting criteria (>=0.75) (BP4 not met). Functional studies indicated subcellular mislocalization of the mutant protein (PMID: 25688877) and decreased receptor-mediated signaling (PMID: 12045205) (PS3 met). At least five unrelated probands have been reported in the literature (PMID: 11115378, 21801371, 27587546, 32634488, 32966279), meeting the PS4 threshold of >4 probands. Alternative missense variants have been reported in the same location but these variants are pending expert panel curation and PM5 is not scored at this time. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS4_strong, PS3_strong, PM1_ moderate, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic ✓ concordant with ClinVar · top 4% in BMPR2
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -13.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, 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.Cys420Arg
Coding: c.1258T>C
MANE Select: NM_001204
dbSNP: rs1085307324
Type: single nucleotide variant
Location: chr2:202532714 (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

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.Cys420Phe Likely 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-cys420arg (accessed [today's date]).

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