MED23

Chr 6AR

mediator complex subunit 23

NCBI Gene: 9439 ENSG00000112282 UniProt: Q9ULK4

Required for transcriptional activation subsequent to the assembly of the pre-initiation complex (By similarity). 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 pre-initiation complex with RNA polymerase II and the general transcription factors. Required for transcriptional activation by adenovirus E1A protein. Required for ELK1-dependent transcriptional activation in response to activated Ras signaling

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 18, with or without epilepsyMIM #614249

543

ClinVar variants

120

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— MED23

🧬

Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ARModerate

Moderate evidence — consider for supplementary testing

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

120 Pathogenic / Likely Pathogenic· 198 VUS of 543 total submissions

💊

Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

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.

0.50LOEUF

pLI 0.000

Z-score 5.09

OE 0.36 (0.27–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

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.

4.73Z-score

OE missense 0.51 (0.47–0.55)

369 obs / 728.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

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.0.36 (0.27–0.50)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.51 (0.47–0.55)

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.0.90

0≤1.21.6

LoF obs/exp: 27 / 74.4Missense obs/exp: 369 / 728.1Syn Z: 1.21