MED12

Chr X

mediator complex subunit 12

Also known as: ARC240, CAGH45, FGS1, HDKR, HOPA, Kto, MED12S, OHDOX

NCBI Gene: 9968ENSG00000184634UniProt: Q93074

The initiation of transcription is controlled in part by a large protein assembly known as the preinitiation complex. A component of this preinitiation complex is a 1.2 MDa protein aggregate called Mediator. This Mediator component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates. The MED12 protein is essential for activating CDK8 kinase. Defects in this gene cause X-linked Opitz-Kaveggia syndrome, also known as FG syndrome, and Lujan-Fryns syndrome. [provided by RefSeq, Aug 2009]

Primary Disease Associations & Inheritance

UniProtOpitz-Kaveggia syndrome
UniProtIntellectual developmental disorder, X-linked, syndromic, Lujan-Fryns type
UniProtOhdo syndrome, X-linked
UniProtHardikar syndrome
403
ClinVar variants
14
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MED12
🧬
Gene-Disease Validity (ClinGen)
MED12-related intellectual disability syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 133 VUS of 403 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.07LOEUF
pLI 1.000
Z-score 8.53
OE 0.02 (0.01–0.07)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
6.58Z-score
OE missense 0.38 (0.35–0.42)
343 obs / 897.8 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.02 (0.01–0.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.38 (0.35–0.42)
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.0.91
0≤1.21.6
LoF obs/exp: 2 / 88.7Missense obs/exp: 343 / 897.8Syn Z: 1.25

ClinVar Variant Classifications

403 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic7
VUS133
Likely Benign207
Benign29
Conflicting20
7
Pathogenic
7
Likely Pathogenic
133
VUS
207
Likely Benign
29
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
7
0
7
Likely Pathogenic
3
3
1
0
7
VUS
2
104
23
4
133
Likely Benign
0
11
66
130
207
Benign
0
4
22
3
29
Conflicting
—20
Total5122119137403

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

View in ClinVar →

Protein Context — Lollipop Plot

MED12 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MED12-related developmental disorder

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

MED12-related Opitz-Kaveggia syndrome

definitive
Monoallelic X HemizygousUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

MED12-related Lujan-Fryns syndrome

definitive
Monoallelic X HemizygousUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — MED12
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Enhanced T cell effector activity by targeting the Mediator kinase module.
Freitas KA et al.·Science
2022
Single-cell sequencing reveals novel cellular heterogeneity in uterine leiomyomas.
Goad J et al.·Hum Reprod
2022
MED12 related disorders.
Graham JM Jr et al.·Am J Med Genet A
2013Review
Eye and ocular adnexa manifestations of MED12-related disorders.
Shah A et al.·Ophthalmic Genet
2022
Frequency of MED12 Mutation in Relation to Tumor and Patient's Clinical Characteristics: a Meta-analysis.
He C et al.·Reprod Sci
2022Meta-analysis
MED12-Related (Neuro)Developmental Disorders: A Question of Causality.
Plassche SV et al.·Genes (Basel)
2021Review
Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma.
Berta DG et al.·Nature
2021
Insights into the regulatory role and clinical relevance of mediator subunit, MED12, in human diseases.
Srivastava S et al.·J Cell Physiol
2021Review
MED12 and CDK8/19 Modulate Androgen Receptor Activity and Enzalutamide Response in Prostate Cancer.
Andolfi C et al.·Endocrinology
2024
Genomic Landscape of Malignant Phyllodes Tumors Identifies Subsets for Targeted Therapy.
Bansal R et al.·JCO Precis Oncol
2024
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools