Is BMPR2 p.Glu427Asp (c.1281A>T) pathogenic?

BMPR2 p.Glu427Asp (c.1281A>T) is classified Likely benign in BMPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely benign (0.1321); Very rare (popmax 0.00119%, nfe); Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Glu427Asp (c.1281A>T)?

BMPR2 p.Glu427Asp (c.1281A>T) is associated with Primary pulmonary hypertension (ClinVar).

How common is BMPR2 p.Glu427Asp (c.1281A>T) in the general population?

BMPR2 p.Glu427Asp (c.1281A>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about BMPR2 p.Glu427Asp (c.1281A>T)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

BMPR2 p.Glu427Asp

c.1281A>T · VCV4753517

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.344	indeterminate
SaProt	LLR -7.94	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 3	GERP -0.096, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	21.6	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 0.00119% European (non-Finnish) · 14/1,179,900 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,878 alleles · very rare

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.Glu427Asp
Coding: c.1281A>T
MANE Select: NM_001204
Type: single nucleotide variant
Location: chr2:202542315 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 427: 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

Similar variants

BMPR2 p.Glu427Lys Uncertain significance ★ ⚠ same residue
BMPR2 c.1128+1G>A Pathogenic ★★ same condition
BMPR2 c.1128+1G>C Pathogenic ★★ same condition
BMPR2 c.621+1G>T Pathogenic/Likely pathogenic ★★ same condition
BMPR2 c.853-2A>G Pathogenic ★★ same condition
BMPR2 p.Arg147Ter Pathogenic ★★ same condition
BMPR2 p.Arg213Ter Pathogenic ★★ same condition
BMPR2 p.Arg491Trp 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-glu427asp (accessed [today's date]).

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