Is BMPR2 p.Leu340Pro (c.1019T>C) pathogenic?

BMPR2 p.Leu340Pro (c.1019T>C) is classified Likely pathogenic in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2026-04-09). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Leu340Pro (c.1019T>C)?

BMPR2 p.Leu340Pro (c.1019T>C) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Leu340Pro (c.1019T>C) in the general population?

BMPR2 p.Leu340Pro (c.1019T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Leu340Pro (c.1019T>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

BMPR2 p.Leu340Pro

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.1019T>C · rs1085307289 · VCV425864

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9989 · 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

Curation rationale (ClinGen, verbatim)

The BMPR2 c.1019T>C (p.Leu340Pro) variant is an exonic variant which is located in exon 8. This variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2_supporting met). The variant is located in a well-established protein kinase domain (PM1_met) and has been identified in 3 apparently unrelated individuals with PAH to date (PMIDs 18356561, 19555857, 32581362; PS4_supporting met). BMPR2 has a low rate of benign missense variation and missense variants are a common mechanism of disease (PP2). In silico prediction is consistent with a pathogenic effect ((REVEL score 0.980 (>0.75; PP3 met)). PP1 was not assessed due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for pulmonary arterial hypertension (PS1, PM5 not assessed). In summary, this variant meets the criteria to be classified as a 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	0.9989	likely pathogenic ✓ concordant with ClinVar · top 2% in BMPR2
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -16.85	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 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	29.8	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.Leu340Pro
Coding: c.1019T>C
MANE Select: NM_001204
dbSNP: rs1085307289
Type: single nucleotide variant
Location: chr2:202530845 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 340: 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.Leu340= 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
BMPR2 c.247+1G>A Likely 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-leu340pro (accessed [today's date]).

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