MED12

Chr X

mediator complex subunit 12

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

NCBI Gene: 9968 ENSG00000184634 UniProt: Q93074

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.

GeneReviews 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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtOpitz-Kaveggia syndrome

UniProtIntellectual developmental disorder, X-linked, syndromic, Lujan-Fryns type

UniProtOhdo syndrome, X-linked

UniProtHardikar syndrome

Clinical highlights

Gene-disease validity (ClinGen)

MED12-related intellectual disability syndrome · XLDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.07

LOEUF· LoF intol.

LOF

Mechanism· G2P

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GeneReview available — MED12