Is BMPR2 p.Arg419Ser (c.1257A>T) pathogenic?

BMPR2 p.Arg419Ser (c.1257A>T) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 2 submitters; last evaluated 2025-01-03). AlphaMissense: likely pathogenic (0.9777); Very rare (popmax 0.00223%, eas); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Arg419Ser (c.1257A>T)?

BMPR2 p.Arg419Ser (c.1257A>T) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Arg419Ser (c.1257A>T) in the general population?

BMPR2 p.Arg419Ser (c.1257A>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BMPR2 p.Arg419Ser (c.1257A>T)?

AlphaMissense predicts likely pathogenic (score 0.9777) — an in-silico prediction, not a clinical call.

BMPR2 p.Arg419Ser

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.1257A>T · rs1085307323 · VCV425905

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PM2_Supporting PM1_moderate

Curation rationale (ClinGen, verbatim)

BMPR2 c.1257A>T is a missense variant predicted to cause substitution of arginine to serine at amino acid position 419 (p.Arg419Ser). The variant is absent from gnomAD v2.1.1 controls and found at a maximum allele frequency of 0.000022 in gnomAD v4.1.0 in the East Asian ancestry group, meeting PM2_supporting criterion of <0.01% (BA1 and BS1 not met). The REVEL score of 0.59 does not meet BP4 (<=0.25) or PP3 (>=0.75) criteria. This variant resides within the critical kinase domain (PM1_moderate met). Co-segregation/case, experimental criteria, and alternative missense variants at the same location were not evaluated due to lack of reported evidence. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PM1_moderate (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	0.9777	likely pathogenic · top 10% in BMPR2
REVEL	0.59	indeterminate
SaProt	LLR -13.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -4.8, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,840 alleles

Overall 6.2e-05% 1/1,613,172 alleles · very rare exomes 1/1,460,836 · genomes 0/152,336 · joint denominator

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.Arg419Ser
Coding: c.1257A>T
MANE Select: NM_001204
dbSNP: rs1085307323
Type: single nucleotide variant
Location: chr2:202532713 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 419: 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

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.Arg419dup Likely pathogenic same residue
BMPR2 p.Arg419Lys Uncertain significance ★ 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-arg419ser (accessed [today's date]).

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