MED12

protein-coding

mediator complex subunit 12, the group of Mediator complex

Gene summary

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]

Previous symbols:

TNRC11
FGS1

MANE transcript

NM_005120.3

Inheritance

ClinVar variants

P:111U:1044B:835

Top phenotype

Hardikar syndrome

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chrX:71,118,543-71,144,103

External References & Databases

Ensembl (ENSG00000184634)

Transcript & Mutation Effects

hg38 • Region Span ~25.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

blepharophimosis - intellectual disability syndrome, MKB typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010477

Submitter: Labcorp Genetics (formerly Invitae)

FG syndrome 1SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010590

Submitter: Orphanet

X-linked intellectual disability with marfanoid habitusSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010655

Submitter: Orphanet

cholestasis-pigmentary retinopathy-cleft palate syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0012997

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0700092

Submitter: G2P

blepharophimosis - intellectual disability syndrome, MKB typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010477

Submitter: Orphanet

MED12-related intellectual disability syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100000

Submitter: ClinGen

MED12 is a component of the multisubunit Mediator complex, which is involved in transcriptional regulation of RNA polymerase II-dependent genes. *MED12* was first reported in relation to X-linked *MED12*-related intellectual disability syndrome in 2007 (Risheg et al., PMID: 17334363; Schwartz et al., PMID: 17369503). Missense variants in *MED12* have been reported in individuals with several disease entities within the spectrum of X-linked recessive syndromic intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism or inheritance pattern underlying the disease entities: 1) Opitz-Kaveggia syndrome, also known as FG syndrome (MIM:305450), 2) Lujan-Fryns syndrome (MIM:309520), and 3) X-linked Ohdo syndrome (MIM:300895). Therefore, these entities were lumped into one disease entity, X-linked *MED12*-related intellectual disability syndrome. The most penetrant phenotype shared by these syndromes is intellectual disability, with other features such as dysgenesis or agenesis of the corpus callosum, blepharophimosis, marfanoid habitus, and anal anomalies having variable expressivity. In all three of these syndromes, carrier females are typically unaffected, but there are a few reports of females with mild intellectual disability and/or facial dysmorphism. More recently, males with intellectual disability without a distinct syndrome, and female patients with *de novo* missense variants or protein truncating variants in *MED12* have also been reported (e.g., PMIDs: 24039113, 30006928, 31536828, 33244165). Eighteen variants in 30 male probands (17 missense and 1 frameshift) and 3 variants in 3 female probands (1 *de novo* nonsense and 2 missense) are included in this curation. Several missense variants are recurrent, including p.Arg961Trp in 10 unrelated individuals in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by biochemical function and protein interactions as part of the kinase module of the Mediator complex, functional studies, and an animal model. In summary, there is definitive evidence supporting the relationship between *MED12* and X-linked *MED12*-related intellectual disability syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 18, 2018. It was reevaluated on October 15, 2025 (SOP Version 11). Although further experimental evidence was added, the classification did not change.

X-linked intellectual disability with marfanoid habitusSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010655

Submitter: Labcorp Genetics (formerly Invitae)

X-linked intellectual disability with marfanoid habitusDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010655

Submitter: G2P

FG syndrome 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010590

Submitter: Labcorp Genetics (formerly Invitae)

FG syndrome 1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010590

Submitter: G2P

MED12-related intellectual disability syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0100000

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hardikar syndromeXL

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Among other findings in Hardikar syndrome, congenital cardiovascular anomalies may occur, and early identificaiton and management may be beneficial

Comments: Aortic root dilatation and ventricular septal defect were reported in one individual and his maternal uncle

Refs: 4365204; 6711603; 3322000; 10405444; 10508979; 17036352; 17334363; 17369503; 18973276; 19938245; 20301719; 20507344; 20981778; 23395478; 33244166

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MED12 variants in ClinVar

42 Conditions Cataloged

FG syndromeTotal: 1592

not providedTotal: 711

Familial thoracic aortic aneurysm and aortic dissectionTotal: 698

not specifiedTotal: 233

MED12-Related DisordersTotal: 130

FG syndrome 1Total: 114

Blepharophimosis - intellectual disability syndrome, MKB typeTotal: 69

X-linked intellectual disability with marfanoid habitusTotal: 62

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005120.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			45 clinvar	641 clinvar	19 clinvar	705
missense	5 clinvar	52 clinvar	912 clinvar	161 clinvar	13 clinvar	1143
nonsense	12 clinvar	10 clinvar	24 clinvar			46
start loss						0
frameshift	8 clinvar	10 clinvar	6 clinvar			24
splice donor/acceptor (+/-2bp)	2 clinvar	12 clinvar	57 clinvar	1 clinvar		72
Total	27	84	1044	803	32	1990

Highest pathogenic variant AF is 0.000005477511

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005120.3	RefSeq	NP_005111.2	45	MANE Select
ENST00000374080.8	Ensembl	ENSP00000363193.3	45	MANE Select
ENST00000333646.11	Ensembl	ENSP00000333125.8	45	Standard
ENST00000333646.12	Ensembl	ENSP00000333125.8	45	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
med12	Danio rerio	Structure: neutrophil Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

med12

Danio rerio

Structure: neutrophil

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone signaling pathway - Homo sapiens (human)
WNT-Ncore
Developmental Biology
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

neural tube closure
regulation of transcription by RNA polymerase II
transcription initiation from RNA polymerase II promoter
endoderm development
heart development

Molecular Function

RNA polymerase II distal enhancer sequence-specific DNA binding
chromatin binding
transcription coregulator activity
transcription coactivator activity
protein binding

Cellular Component

ubiquitin ligase complex
nucleus
nucleoplasm
membrane
mediator complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374080
Coding exons: 45
Length: 23898
Individuals with no LoFs: 121517
Homozygous LoFs: 1
Heterozygous LoFs: 0
Defined: 121518
p: 0.00000411

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	6.58	343	898	0.382	0.0000742	14199
Missense (PolyPhen)		66	275	0.24		4257
Synonymous	1.25	314	343	0.914	0.0000269	4324
Loss of Function	8.53	2	88.7	0.0226	0.00000676	1318

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000013	0.0000092	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway. {ECO:0000269|PubMed:16565090, ECO:0000269|PubMed:16595664, ECO:0000269|PubMed:17000779}.;
Disease: DISEASE: Lujan-Fryns syndrome (LUJFRYS) [MIM:309520]: Clinically, Lujan-Fryns syndrome can be distinguished from Opitz-Kaveggia syndrome by tall stature, hypernasal voice, hyperextensible digits and high nasal root. {ECO:0000269|PubMed:17369503}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ohdo syndrome, X-linked (OHDOX) [MIM:300895]: A syndrome characterized by mental retardation, feeding problems, and distinctive facial appearance with coarse facial features, severe blepharophimosis, ptosis, a bulbous nose, micrognathia and a small mouth. Dental hypoplasia and deafness can be considered as common manifestations of the syndrome. Male patients show cryptorchidism and scrotal hypoplasia. {ECO:0000269|PubMed:23395478}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.306

Intolerance Scores

RVIS EVS: -1
RVIS percentile EVS: 8.47

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.952

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium