Is BMPR2 p.Ile46Val (c.136A>G) pathogenic?

BMPR2 p.Ile46Val (c.136A>G) is classified Uncertain significance in BMPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-15). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.004%, afr); Associated with pulmonary hypertension, primary, 1.

What condition is associated with BMPR2 p.Ile46Val (c.136A>G)?

BMPR2 p.Ile46Val (c.136A>G) is associated with pulmonary hypertension, primary, 1, pulmonary venoocclusive disease 1 (ClinVar).

How common is BMPR2 p.Ile46Val (c.136A>G) in the general population?

BMPR2 p.Ile46Val (c.136A>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about BMPR2 p.Ile46Val (c.136A>G)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

BMPR2 p.Ile46Val

c.136A>G · rs759804753 · VCV195138

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pulmonary hypertension, primary, 1

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.91	donor gain · deltas
Pangolin	Δ0.80	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,916 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,998 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.Ile46Val
Coding: c.136A>G
MANE Select: NM_001204
dbSNP: rs759804753
Type: single nucleotide variant
Location: chr2:202464868 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 46: a disulfide bond; a turn

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.Ile46Thr Uncertain significance ★ ⚠ same residue
BMPR2 p.Ile46Leu 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

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-ile46val (accessed [today's date]).

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