Is BMPR2 p.Val339Asp (c.1016T>A) pathogenic?

BMPR2 p.Val339Asp (c.1016T>A) is classified Likely pathogenic in BMPR2 (ClinVar, Expert panel, 2 submitters; last evaluated 2026-04-09). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Val339Asp (c.1016T>A)?

BMPR2 p.Val339Asp (c.1016T>A) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Val339Asp (c.1016T>A) in the general population?

BMPR2 p.Val339Asp (c.1016T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Val339Asp (c.1016T>A)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

BMPR2 p.Val339Asp

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.1016T>A · rs1085307288 · VCV425863

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9992 · 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_met PP2 PP3_met

Curation rationale (ClinGen, verbatim)

The NM_001204.7(BMPR2) c.1016T>A (p.Val339Asp) variant is harboured in exon 8 of the gene, encoding the functionally relevant catalytic kinase domain (PM1_met). The variant has been twice reported in the Japanese population in one IPAH and one HPAH subject (PMID: 23579436 and PMID: 23675998), (PS4_supporting). This variant is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). BMPR2 has a low rate of benign missense variation (misZ = 3.28, gnomAD v4.1) and missense variants are a common mechanism of disease (PP2). The REVEL prediction algorithm score is 0.967, AlphaMissense is 0.9992 indicating pathogenicity (PP3_met). PP1 and PS2 were not assessed due to absence of co-segregation data and parental data respectively. No other amino acid change at the same position has been reported for PAH (PS1 and PM5 not assessed). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting, PP2, PP3, PS4_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	0.9992	likely pathogenic ✓ concordant with ClinVar · top 1% in BMPR2
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -16.83	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 6.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	31.0	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.Val339Asp
Coding: c.1016T>A
MANE Select: NM_001204
dbSNP: rs1085307288
Type: single nucleotide variant
Location: chr2:202530842 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 339: 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 β-strand

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.Val339Ala Uncertain significance ★ ⚠ same residue
BMPR2 p.Val339= 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

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-val339asp (accessed [today's date]).

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