GREM2

Chr 1AD

gremlin 2, DAN family BMP antagonist

ENSG00000180875UniProt: Q9H772

Cytokine that inhibits the activity of BMP2 and BMP4 in a dose-dependent manner, and thereby modulates signaling by BMP family members. Contributes to the regulation of embryonic morphogenesis via BMP family members. Antagonizes BMP4-induced suppression of progesterone production in granulosa cells

Primary Disease Associations & Inheritance

Tooth agenesis, selective, 9MIM #617275
AD
0
ClinVar variants
0
Pathogenic / LP
0.03
pLI score
1
Active trials
Clinical Summary— GREM2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.23Z-score
OE missense 0.68 (0.56–0.82)
78 obs / 115.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.49 (0.22–1.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.56–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.76
0≤1.21.6
LoF obs/exp: 3 / 6.1Missense obs/exp: 78 / 115.2Syn Z: 1.38

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

GREM2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Tooth agenesis, selective, 9

MIM #617275

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic Aspects of Tooth Agenesis.
Modafferi C et al.·Genes (Basel)
2025Review
Tooth agenesis: What do we know and is there a connection to cancer?
Bonczek O et al.·Clin Genet
2021Review
miR-122-5p targets GREM2 to protect against glucocorticoid-induced endothelial damage through the BMP signaling pathway.
Huang X et al.·Mol Cell Endocrinol
2022
BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction.
Sanders LN et al.·Circ Res
2016
GREM2 nucleotide variants and the risk of tooth agenesis.
Mostowska A et al.·Oral Dis
2018
Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis.
Magruder S et al.·Orthod Craniofac Res
2018
ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3.
Lin I et al.·BMC Med Genomics
2024
Association of Gremlin-2 gene polymorphisms with osteoporosis risk in Chinese postmenopausal women.
Feng Y et al.·Biosci Rep
2020
Association Between Circulating Gremlin 2 and β-Cell Function Among Participants With Prediabetes and Type 2 Diabetes.
Ni M et al.·J Diabetes
2025
Development and validation of a novel immune-related prognostic model and the potential metastatic mechanism in synovial sarcoma.
Huang Y et al.·Front Immunol
2024Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Integrative Transcriptome and Machine Learning Analysis Uncovers Critical STAT3/GREM2 Signaling Mechanisms in Dexamethasone Treatment of Hashimoto's Thyroiditis.
Zeng H et al.·ACS Omega
2025🔓 Open AccessFunctional
Overexpression of miR-671-3p alleviates postmenopausal osteoporosis by targeting GREM2 to activate BMP2/SMAD signaling pathway.
Liang Y et al.·Hereditas
2025🔓 Open Access
Mesenchymal Stem Cells Mediated Suppression of GREM2 Inhibits Renal Epithelial-Mesenchymal Transition and Attenuates the Progression of Diabetic Kidney Disease.
Ko MS et al.·Int J Stem Cells
2025🔓 Open Access
6-Shogaol alleviates high-fat diet induced hepatic steatosis through miR-3066-5p/Grem2 pathway.
Jiao W et al.·Food Chem
2024
GREM2 inactivation increases trabecular bone mass in mice.
Nilsson KH et al.·Sci Rep
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
ALS (Amyotrophic Lateral Sclerosis)

This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β/SMAD-driven Astrocytic and Fibrotic Signaling

NOT YET RECRUITING
NCT07321860Phase PHASE2, PHASE3Gipfel Life Sciences GmbHStarted 2026-06-30
Galunisertib + Nerandomilast Combination

External Resources

Links to major genomics databases and tools