GREM2

Chr 1AD

gremlin 2, DAN family BMP antagonist

Also known as: CKTSF1B2, DAND3, PRDC, STHAG9

NCBI Gene: 64388ENSG00000180875UniProt: Q9H772OMIM: 608832

This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. [provided by RefSeq, Jul 2008]

OMIMResearchGenerating clinical summary…
MultiplemechanismADLOEUF 1.271 OMIM phenotype
Clinical Summary— GREM2
🧬
Gene-Disease Validity (ClinGen)
tooth agenesis, selective, 9 · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
1 unique Pathogenic / Likely Pathogenic· 22 VUS of 26 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
1.27LOEUF
pLI 0.032
Z-score 1.15
OE 0.49 (0.22–1.27)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?
1.23Z-score
OE missense 0.68 (0.56–0.82)
78 obs / 115.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.49 (0.22–1.27)
0≤0.351.4
Missense OE?0.68 (0.56–0.82)
0≤0.61.4
Synonymous OE?0.76
0≤1.21.6
LoF obs/exp: 3 / 6.1Missense obs/exp: 78 / 115.2Syn Z: 1.38

This gene — mechanism propensity

DN
0.6259th %ile
GOF
0.3094th %ile
LOF
0.3843th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFOverall, these data support the hypothesis that GREM2 regulates cardiac rhythm in the atrium, and establish that higher than normal GREM2 activity, either by overexpression or gain-of-function mutations such as the Q76E variant, have arrhythmogenic potential.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

  1. 1.PMID 23223679 ↗

ClinVar Variant Classifications

26 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
VUS22
Likely Benign1
Benign1
Conflicting1
1
Pathogenic
22
VUS
1
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
0
0
1
Likely Pathogenic
0
0
0
0
0
VUS
0
21
1
0
22
Likely Benign
0
0
0
1
1
Benign
0
0
1
0
1
Conflicting
—1
Total0222126

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

63 pathogenic / likely-pathogenic (of 77) ClinVar copy-number / structural variants overlap GREM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

GREM2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients