RUNX2

Chr 6AD

RUNX family transcription factor 2

Also known as: AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD, OSF-2, OSF2

NCBI Gene: 860 ENSG00000124813 UniProt: Q13950 OMIM: 600211

The encoded transcription factor is essential for osteoblastic differentiation and skeletal morphogenesis, binding DNA to regulate skeletal gene expression. Heterozygous loss-of-function mutations cause cleidocranial dysplasia and related skeletal disorders including metaphyseal dysplasia with maxillary hypoplasia, following an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.344 OMIM phenotypes

Clinical Summary— RUNX2

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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.

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ClinVar Variants

189 unique Pathogenic / Likely Pathogenic· 293 VUS of 684 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RUNX2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.60Z-score

OE missense 0.74 (0.66–0.83)

225 obs / 303.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.34)

0≤0.351.4

Missense OE?0.74 (0.66–0.83)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 3 / 22.6Missense obs/exp: 225 / 303.6Syn Z: -1.88

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRUNX2-related cleidocranial dysplasiaLOFAD

This gene — mechanism propensity

0.5279th %ile

GOF

0.2796th %ile

LOF

0.82top 5%

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

LOFprediction above median · 1 literature citation · 68% of P/LP variants are LoF · LOEUF 0.34

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNUnlabeled oligonucleotide or truncated, dominant negative RUNX2 proteins were competitive inhibitors of RUNX2 DNA binding.1

GOFTransfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function.2

LOFRUNX2 mRNA was downregulated by approximately 50% in the patient's cartilage, suggesting that the mutation causes haploinsufficiency.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

684 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic138

Likely Pathogenic51

VUS293

Likely Benign119

Benign51

Conflicting17

138

Pathogenic

Likely Pathogenic

293

VUS

119

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	98	22	17	1	138
Likely Pathogenic	31	20	0	0	51
VUS	5	222	65	1	293
Likely Benign	0	11	38	70	119
Benign	0	0	46	5	51
Conflicting	—				17
Total	134	275	166	77	669

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap RUNX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →