Is BMPR2 p.Val348Ile (c.1042G>A) pathogenic?

BMPR2 p.Val348Ile (c.1042G>A) is classified Likely benign in BMPR2 (ClinVar, Expert panel, 8 submitters; last evaluated 2024-05-03). AlphaMissense: likely benign (0.2008); Rare (popmax 0.399%, eas); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Val348Ile (c.1042G>A)?

BMPR2 p.Val348Ile (c.1042G>A) is associated with pulmonary arterial hypertension, tooth agenesis, selective, 1, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Val348Ile (c.1042G>A) in the general population?

BMPR2 p.Val348Ile (c.1042G>A) is rare (popmax 0.399%, eas) (gnomAD).

What do computational predictors say about BMPR2 p.Val348Ile (c.1042G>A)?

AlphaMissense predicts likely benign (score 0.2008) — an in-silico prediction, not a clinical call.

BMPR2 p.Val348Ile

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.1042G>A · rs201067849 · VCV333642

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2008 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.399%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PS3_Supporting BS1

Curation rationale (ClinGen, verbatim)

The NM_001204.7(BMPR2) c.1042G>A variant is a missense variant predicted to cause a valine to isoleucine substitution at amino acid 348 (p.Val348Ile). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.88% (62/7044) alleles in the “Other” East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold >0.1% for BS1, and therefore meets this criterion (BS1). PP3 was not met. The computational predictor REVEL gives a score of 0.744 which is below the threshold of >0.75 for pathogenicity. Densitometry analysis indicated a modest reduction in p-SMAD levels but this was not consolidated by additional experimental analysis (PS3_supporting). In summary the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PS3_supporting (VCEP specification version 1.1, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.2008	likely benign
REVEL	0.744	pathogenic-leaning
SaProt	LLR -8.78	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 2.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	26.2	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 0.399% East Asian · 179/44,876 alleles

Filtering AF 0.351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.333%

Overall 0.0121% 195/1,614,064 alleles · rare exomes 159/1,461,786 · genomes 36/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.399%	251
Remaining individualsnot grpmax-eligible	0.0128%	7,812
South Asian	0.0011%	91,076
European (non-Finnish)	0.000593%	168,566

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.Val348Ile
Coding: c.1042G>A
MANE Select: NM_001204
dbSNP: rs201067849
Type: single nucleotide variant
Location: chr2:202530868 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 348: 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); a β-strand

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: tooth agenesis, selective, 1 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.Val348= 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
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-val348ile (accessed [today's date]).

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