Is BMPR2 p.Met174Arg (c.521T>G) pathogenic?

BMPR2 p.Met174Arg (c.521T>G) is classified Uncertain significance in BMPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). AlphaMissense: ambiguous (0.4389); Very rare (popmax 8.51e-05%, nfe); Associated with pulmonary hypertension, primary, 1.

What condition is associated with BMPR2 p.Met174Arg (c.521T>G)?

BMPR2 p.Met174Arg (c.521T>G) is associated with pulmonary hypertension, primary, 1, pulmonary venoocclusive disease 1 (ClinVar).

How common is BMPR2 p.Met174Arg (c.521T>G) in the general population?

BMPR2 p.Met174Arg (c.521T>G) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about BMPR2 p.Met174Arg (c.521T>G)?

AlphaMissense predicts ambiguous (score 0.4389) — an in-silico prediction, not a clinical call.

BMPR2 p.Met174Arg

c.521T>G · VCV3585260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4389 · ACMG-weighted

gnomAD v4.1

Rare

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

Conditions

pulmonary hypertension, primary, 1

Computational evidence

Protein change
AlphaMissense	0.4389	ambiguous
REVEL	0.516	indeterminate
SaProt	LLR -3.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	23.8	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

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,870 alleles

Overall 6.22e-05% 1/1,607,698 alleles · very rare exomes 1/1,455,386 · genomes 0/152,312 · joint denominator

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.Met174Arg
Coding: c.521T>G
MANE Select: NM_001204
Type: single nucleotide variant
Location: chr2:202513821 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB

Full BMPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pulmonary hypertension, primary, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pulmonary venoocclusive disease 1

Similar variants

BMPR2 p.Met174Thr 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-met174arg (accessed [today's date]).

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