MED13

Chr 17

mediator complex subunit 13

Also known as: ARC250, DRIP250, HSPC221, MRD61, THRAP1, TRAP240

NCBI Gene: 9969 ENSG00000108510 UniProt: Q9UHV7

The MED13 protein is a component of the mediator transcriptional coactivator complex that regulates gene expression by interacting with RNA polymerase II and forming a sub-complex with MED12, cyclin C, and CDK8 that can negatively regulate transcription. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder. The gene is extremely intolerant to loss-of-function variants, indicating haploinsufficiency as the mechanism of pathogenicity.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional coactivator complex thought to be required for the expression of almost all genes. The mediator complex is recruited by transcriptional activators or nuclear receptors to induce gene expression, possibly by interacting with RNA polymerase II and promoting the formation of a transcriptional pre-initiation complex. The product of this gene is proposed to form a sub-complex with MED12, cyclin C, and CDK8 that can negatively regulate transactivation by mediator. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtIntellectual developmental disorder, autosomal dominant 61

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2022

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

0.03

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.03LOEUF

pLI 1.000

Z-score 9.19

OE 0.00 (0.00–0.03)

Highly constrained

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

Missense Constraint?

2.62Z-score

OE missense 0.78 (0.74–0.82)

871 obs / 1117.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.03)

0≤0.351.4

Missense OE?0.78 (0.74–0.82)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 0 / 98.4Missense obs/exp: 871 / 1117.8Syn Z: -1.38

Background carrier burden — how many people carry a rare variant somewhere in MED13?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 33

2,367 rare PASS variants

Rare truncating (LoF)

1 in 2,100

52 rare PASS variants

Rare synonymous (reference)

1 in 46

1,019 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MED13. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 41	1 in 2,100
South Asian	~43k	1 in 28	1 in 1,700
Remaining (unassigned)	~30k	1 in 27	1 in 1,700
European (Finnish)	~27k	1 in 100	1 in 4,300
Admixed American	~22k	1 in 35	1 in 1,200
African / African American	~21k	1 in 27	1 in 1,200
East Asian	~20k	1 in 37	1 in 3,200
Ashkenazi Jewish	~13k	1 in 100	≈ 1 in 5,100
Middle Eastern	~2,884	1 in 30	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.