RUNX2

Chr 6AD

RUNX family transcription factor 2

NCBI Gene: 860ENSG00000124813UniProt: Q13950

Transcription factor involved in osteoblastic differentiation and skeletal morphogenesis (PubMed:28505335, PubMed:28703881, PubMed:28738062). Essential for the maturation of osteoblasts and both intramembranous and endochondral ossification. CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, osteocalcin, osteopontin, bone sialoprotein, alpha 1(I) collagen, LCK, IL-3 and GM-CSF promoters. In osteoblasts, supports transcription activation: synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE) (By similarity). Inhibits KAT6B-dependent transcriptional activation

Primary Disease Associations & Inheritance

Cleidocranial dysplasiaMIM #119600
AD
Cleidocranial dysplasia, forme fruste, dental anomalies onlyMIM #119600
AD
Cleidocranial dysplasia, forme fruste, with brachydactylyMIM #119600
AD
Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactylyMIM #156510
AD
585
ClinVar variants
169
Pathogenic / LP
0.95
pLI score· haploinsufficient
4
Active trials
Clinical Summary— RUNX2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
169 Pathogenic / Likely Pathogenic· 270 VUS of 585 total submissions
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.34LOEUF
pLI 0.949
Z-score 3.82
OE 0.13 (0.06–0.34)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
1.60Z-score
OE missense 0.74 (0.66–0.83)
225 obs / 303.6 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.0.13 (0.06–0.34)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.66–0.83)
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.1.21
0≤1.21.6
LoF obs/exp: 3 / 22.6Missense obs/exp: 225 / 303.6Syn Z: -1.88

ClinVar Variant Classifications

585 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic122
Likely Pathogenic47
VUS270
Likely Benign109
Benign24
Conflicting13
122
Pathogenic
47
Likely Pathogenic
270
VUS
109
Likely Benign
24
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
58
16
47
1
122
Likely Pathogenic
26
17
4
0
47
VUS
3
177
89
1
270
Likely Benign
0
5
36
68
109
Benign
0
0
21
3
24
Conflicting
—13
Total8721519773585

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

View in ClinVar →

Protein Context — Lollipop Plot

RUNX2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RUNX2-related cleidocranial dysplasia

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cleidocranial dysplasia

MIM #119600

Molecular basis of disorder known

Autosomal dominant

Cleidocranial dysplasia, forme fruste, dental anomalies only

MIM #119600

Molecular basis of disorder known

Autosomal dominant

Cleidocranial dysplasia, forme fruste, with brachydactyly

MIM #119600

Molecular basis of disorder known

Autosomal dominant

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly

MIM #156510

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — RUNX2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Osteoarthritis: pathogenic signaling pathways and therapeutic targets.
Yao Q et al.·Signal Transduct Target Ther
2023Review
FOXO1 regulates RUNX2 ubiquitination through SMURF2 in calcific aortic valve disease.
Jiang C et al.·Redox Biol
2024
RUNX2 and Cancer.
Lin TC·Int J Mol Sci
2023Review
Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency in Vascular Smooth Muscle Cells Exacerbates Arterial Calcification.
Ouyang L et al.·Circulation
2022
TET2 suppresses vascular calcification by forming an inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation.
He D et al.·J Clin Invest
2025
Diminished arachidonate 5-lipoxygenase perturbs phase separation and transcriptional response of Runx2 to reverse pathological ventricular remodeling.
Xie S et al.·EBioMedicine
2022Functional
RUNX2 Phase Separation Mediates Long-Range Regulation Between Osteoporosis-Susceptibility Variant and XCR1 to Promote Osteoblast Differentiation.
Zhang Y et al.·Adv Sci (Weinh)
2025
Regulation of Skeletal Development and Maintenance by Runx2 and Sp7.
Komori T·Int J Mol Sci
2024Review
Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation.
Jaruga A et al.·Clin Genet
2016Review
Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2.
Dong Q et al.·Bone Res
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Alveolar Bone Loss Associated Chronic Periodontitis

Clinical Efficacy of 1% Metformin and Alendronate Gel in Adjunct to Fibrin in Chronic Periodontitis

ACTIVE NOT RECRUITING
NCT06856369Phase PHASE4Bahria UniversityStarted 2025-01-22
Platelet rich fibrinMetformin hydrochloride powderalendronate sodium powder
Knee Osteoarthritis

NANOVAE to Treat Knee Osteoarthritis (KOA)

NOT YET RECRUITING
NCT06606561Phase PHASE1, PHASE2Nova Vita LaboratoryStarted 2025-10-01
NANOVAE - Acellular Allogenic Human Amniotic Fluid (hAF)0.9% Sodium Chloride Injection, USP
Gene Expression ProfilingOrthodentic Appliances

Genes Associated With Bone Metabolism in the Saliva During Orthodontic Treatment

ACTIVE NOT RECRUITING
NCT07303647Kurdistan Higher Council of Medical SpecialtiesStarted 2025-10-12
PCR
Adolescent Idiopathic Scoliosis

Identification of Circulating microRNAs in Adolescent Idiopathic Scoliosis

RECRUITING
NCT04746586Istituto Ortopedico RizzoliStarted 2020-07-22
Circulating MiRNA indentification

External Resources

Links to major genomics databases and tools