MED12

Chr XXLDXLR

mediator complex subunit 12

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

NCBI Gene: 9968 ENSG00000184634 UniProt: Q93074 OMIM: 300188

The MED12 protein is essential for activating CDK8 kinase within the Mediator complex, which regulates transcription initiation and reinitiation rates by modulating interactions between Mediator and RNA polymerase II. Loss-of-function mutations cause multiple X-linked intellectual disability syndromes including Opitz-Kaveggia syndrome (FG syndrome), Lujan-Fryns syndrome, Ohdo syndrome, and Hardikar syndrome. The gene shows extreme intolerance to loss-of-function variants and follows X-linked inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLD/XLRLOEUF 0.074 OMIM phenotypes

Clinical Summary— MED12

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Gene-Disease Validity (ClinGen)

MED12-related intellectual disability syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.02 (0.01–0.07)

0≤0.351.4

Missense OE?0.38 (0.35–0.42)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 2 / 88.7Missense obs/exp: 343 / 897.8Syn Z: 1.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMED12-related developmental disorderLOFmonoallelic_X_heterozygous

definitiveMED12-related Opitz-Kaveggia syndromeOTHERXLR

definitiveMED12-related Lujan-Fryns syndromeOTHERXLR

This gene — mechanism propensity

0.17100th %ile

GOF

0.2796th %ile

LOF

0.89top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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