Is BMPR2 p.Ala494Val (c.1481C>T) pathogenic?

BMPR2 p.Ala494Val (c.1481C>T) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 4 submitters; last evaluated 2024-05-03). AlphaMissense: likely pathogenic (0.9793); Ultra-rare (popmax 0.0535%, eas); Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Ala494Val (c.1481C>T)?

BMPR2 p.Ala494Val (c.1481C>T) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Ala494Val (c.1481C>T) in the general population?

BMPR2 p.Ala494Val (c.1481C>T) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

What do computational predictors say about BMPR2 p.Ala494Val (c.1481C>T)?

AlphaMissense predicts likely pathogenic (score 0.9793) — an in-silico prediction, not a clinical call.

BMPR2 p.Ala494Val

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.1481C>T · rs2229778 · VCV333645

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9793 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary arterial hypertension

ClinGen expert panel — Pulmonary Hypertension VCEP

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

PM1 PP3 BS1

Curation rationale (ClinGen, verbatim)

The BMPR2 c.1481C>T variant is a missense variant predicted to result in an alanine to valine substitution at amino acid 494 (p.Ala494Val). The minor allele frequency in gnomAD v2.1.1 controls “Other East Asian" is 0.0016% (11/7044 alleles), which exceeds the PH VCEP threshold of >0.1% for BS1. The variant is located in the kinase domain of BMPR2 (amino acids 203-504) but there is no functional evidence for or against this residue being critical, thus meeting PM1 without modification. The REVEL score is 0.872, exceeding the threshold of 0.75 (PP3). In summary, the variant meets the criteria to be classified as uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PM1, PP3 (VCEP specification version 1.1, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.9793	likely pathogenic · top 10% in BMPR2
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -13.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 20 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0535% East Asian · 24/44,874 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00167% 27/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
South Asian	0.0011%	91,082
European (non-Finnish)	0.000169%	590,012

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.Ala494Val
Coding: c.1481C>T
MANE Select: NM_001204
dbSNP: rs2229778
Type: single nucleotide variant
Location: chr2:202552783 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 494: an α-helix; 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

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

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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
BMPR2 c.247+5G>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-ala494val (accessed [today's date]).

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