Is BMPR2 p.Asn393Ser (c.1178A>G) pathogenic?

BMPR2 p.Asn393Ser (c.1178A>G) is classified Uncertain significance in BMPR2 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-01-03). AlphaMissense: likely pathogenic (0.7974); Absent from gnomAD v4.1; Associated with pulmonary arterial hypertension.

What condition is associated with BMPR2 p.Asn393Ser (c.1178A>G)?

BMPR2 p.Asn393Ser (c.1178A>G) is associated with pulmonary arterial hypertension, pulmonary hypertension, primary, 1 (ClinVar).

How common is BMPR2 p.Asn393Ser (c.1178A>G) in the general population?

BMPR2 p.Asn393Ser (c.1178A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Asn393Ser (c.1178A>G)?

AlphaMissense predicts likely pathogenic (score 0.7974) — an in-silico prediction, not a clinical call.

BMPR2 p.Asn393Ser

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.1178A>G · rs1574494582 · VCV812825

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7974 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

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):

PM2_Supporting PM1_moderate

Curation rationale (ClinGen, verbatim)

The c.1178A>G (p.Asn393Ser) variant is a missense variant harboured in exon 9 of the BMPR2 gene, predicted to cause substitution of asparagine to serine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating critical or non-critical (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.68, AlphaMissense is 0.79, both below our thresholds for pathogenicity (PP3_not met) but above our thresholds for benignity (BP4 not met). The variant has been reported only once in a PAH subject (PMID: 32581362) (PS4 not met). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024).

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

Computational evidence

Protein change
AlphaMissense	0.7974	likely pathogenic
REVEL	0.68	pathogenic-leaning
SaProt	LLR -11.72	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 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 1,719 bp · p 3.4e-08 · regional, not allelic
Overall
CADD	27.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BMPR2
Protein: p.Asn393Ser
Coding: c.1178A>G
MANE Select: NM_001204
dbSNP: rs1574494582
Type: single nucleotide variant
Location: chr2:202532634 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 393: 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

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
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-asn393ser (accessed [today's date]).

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