Is BMPR2 p.Ser301Pro (c.901T>C) pathogenic?

BMPR2 p.Ser301Pro (c.901T>C) is classified Pathogenic in BMPR2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-05-03). AlphaMissense: likely pathogenic (0.9046); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Ser301Pro (c.901T>C)?

BMPR2 p.Ser301Pro (c.901T>C) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Ser301Pro (c.901T>C) in the general population?

BMPR2 p.Ser301Pro (c.901T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Ser301Pro (c.901T>C)?

AlphaMissense predicts likely pathogenic (score 0.9046) — an in-silico prediction, not a clinical call.

BMPR2 p.Ser301Pro

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.901T>C · rs876657748 · VCV228460

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9046 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PM6 PM2_Supporting PS3 PS4 PM1_moderate

Curation rationale (ClinGen, verbatim)

The c.901T>C variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of serine by proline at amino acid 301 (p.Ser301Pro). The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant has been identified in 5 probands, meeting the PH VCEP threshold for PS4 (>4 pro bands; PMIDs 16429395, 18356561, 25917481, 29743074, and PH VCEP internal lab contributors). The variant has been identified as a de novo occurrence in one individual with pulmonary arterial hypertension and unconfirmed parental relationships (PM6; PMID 29743074). Immunostaining in Hela cells transfected with a FLAG-tagged c.901C>T BMPR2 expression construct demonstrated impaired subcellular trafficking of BMPRII (PMID: 25688877) and Western-blot analysis of pulmonary artery smooth muscle cells isolated from a patient with the c.901C>T variant showed no BMP4-induced phosphorylation of Smad1/5/8 (PMID: 19324947), indicating an effect on protein function (PS3). This variant resides in a conserved kinase domain (amino acids 203 – 504) but is not defined as a critical residue by the ClinGen PH VCEP (PM1_moderate). In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.0): PS4, PM6, PM2_Supporting, PS3, PM1_moderate).

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

Computational evidence

Protein change
AlphaMissense	0.9046	likely pathogenic ✓ concordant with ClinVar
REVEL	0.451	indeterminate
SaProt	LLR -13.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	25.1	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.Ser301Pro
Coding: c.901T>C
MANE Select: NM_001204
dbSNP: rs876657748
Type: single nucleotide variant
Location: chr2:202520135 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 301: 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); an α-helix

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.Ser301Cys Uncertain significance ★ ⚠ same residue
BMPR2 p.Ser301Phe 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-ser301pro (accessed [today's date]).

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