Is BMPR2 p.Glu994Asp (c.2982A>C) pathogenic?

BMPR2 p.Glu994Asp (c.2982A>C) is classified Uncertain significance in BMPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-09). AlphaMissense: likely benign (0.0565); Very rare (popmax 0.00267%, afr); Associated with BMPR2-related disorder.

What condition is associated with BMPR2 p.Glu994Asp (c.2982A>C)?

BMPR2 p.Glu994Asp (c.2982A>C) is associated with BMPR2-related disorder (ClinVar).

How common is BMPR2 p.Glu994Asp (c.2982A>C) in the general population?

BMPR2 p.Glu994Asp (c.2982A>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BMPR2 p.Glu994Asp (c.2982A>C)?

AlphaMissense predicts likely benign (score 0.0565) — an in-silico prediction, not a clinical call.

BMPR2 p.Glu994Asp

c.2982A>C · rs912262350 · VCV2631789

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0565 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

BMPR2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0565	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -5.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.61	GERP -3.7, phastCons 0.91
Regional constraint	o/e 0.80	unconstrained · MANE · 169 bp · p 0.093 · regional, not allelic
Overall
CADD	5.341	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 0.00267% African / African-American · 2/75,034 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,890 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.Glu994Asp
Coding: c.2982A>C
MANE Select: NM_001204
dbSNP: rs912262350
Type: single nucleotide variant
Location: chr2:202559811 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 994: a UniProt-annotated variant site (in pph1; changed localization to the plasma membrane); 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

BMPR2-related disorder

Similar variants

BMPR2 p.Glu994Ala Uncertain significance ★ ⚠ same residue
BMPR2 p.Glu994Val Uncertain significance ★ ⚠ same residue
BMPR2 p.Arg321Ter Pathogenic ★★ same condition
BMPR2 p.Arg332Ter Pathogenic ★★ same condition
BMPR2 p.Arg591Ter Pathogenic/Likely pathogenic ★★ same condition
BMPR2 p.Arg597Ter Pathogenic ★★ same condition
BMPR2 p.Cys117Tyr Pathogenic/Likely pathogenic ★★ same condition
BMPR2 p.Gln741Ter Pathogenic/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-glu994asp (accessed [today's date]).

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