Is BMPR2 p.Arg321Ter (c.961C>T) pathogenic?

BMPR2 p.Arg321Ter (c.961C>T) is classified Pathogenic in BMPR2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-10). Very rare (popmax 8.51e-05%, nfe); Associated with BMPR2-related disorder.

What condition is associated with BMPR2 p.Arg321Ter (c.961C>T)?

BMPR2 p.Arg321Ter (c.961C>T) is associated with BMPR2-related disorder, pulmonary arterial hypertension, pulmonary venoocclusive disease 1 (ClinVar).

How common is BMPR2 p.Arg321Ter (c.961C>T) in the general population?

BMPR2 p.Arg321Ter (c.961C>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

BMPR2 p.Arg321Ter

c.961C>T · rs1060502581 · VCV409826

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Conditions

BMPR2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 2.4, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,814 alleles

Overall 6.87e-05% 1/1,456,118 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.Arg321Ter
Coding: c.961C>T
MANE Select: NM_001204
dbSNP: rs1060502581
Type: single nucleotide variant
Location: chr2:202520195 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 321: 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

BMPR2-related disorder

Also linked: pulmonary arterial hypertension pulmonary venoocclusive disease 1 pulmonary hypertension, primary, 1

Similar variants

BMPR2 p.Arg321fs Pathogenic ★ 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-arg321ter (accessed [today's date]).

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