Is BMPR2 p.Leu504= (c.1512T>G) pathogenic?

BMPR2 p.Leu504= (c.1512T>G) is classified Likely benign in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-05-02). Very rare (popmax 0.00415%, nfe); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Leu504= (c.1512T>G)?

BMPR2 p.Leu504= (c.1512T>G) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Leu504= (c.1512T>G) in the general population?

BMPR2 p.Leu504= (c.1512T>G) is very rare (popmax 0.00415%, nfe) (gnomAD).

BMPR2 p.Leu504=

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.1512T>G · rs777417397 · VCV898481

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

BP7 BP4

Curation rationale (ClinGen, verbatim)

The BMPR2 c.1512T>G;p.(leu504=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.0138% (2/14452 alleles) in the North-Western European population, which is lower than the ClinGen Pulmonary Hypertension VCEP threshold of >0.1% for BS1 and >1% for BA1, but higher than the threshold of <0.01% for PM2 (BS1, BA1 and PM2 are not met). BS2 was not met as the variant was not observed as a homozygous allele in gnomAD v2.1.1 controls. BP4 is met based on the computational predictor, CADD, giving a score of 8.3 which is below the threshold of ≤10.0 for BP4. Due to the absence of segregation data, PP1, PM6 and PS2 could not be evaluated. Due to absence of functional data, BS3 and PS3 could not be evaluated. In summary, the variant meets the criteria to be classified as a likely benign variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BP4, BP7 (VCEP specification version 1.1, 1/18/2024).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -5.4, phastCons 0.003
Overall
CADD	3.226	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00415% European (non-Finnish) · 49/1,180,032 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00359% 58/1,614,046 alleles · very rare exomes 55/1,461,884 · genomes 3/152,162 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.00415%	24,082

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu504=
Coding: c.1512T>G
MANE Select: NM_001204
dbSNP: rs777417397
Type: single nucleotide variant
Location: chr2:202552814 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 504: an α-helix; 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.Leu504Phe 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
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-leu504 (accessed [today's date]).

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