MED12L

Chr 3AD

mediator complex subunit 12L

Also known as: NIZIDS, NOPAR, TNRC11L, TRALP, TRALPUSH

NCBI Gene: 116931ENSG00000144893UniProt: Q86YW9

The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery. [provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

Nizon-Isidor syndromeMIM #618872
AD
661
ClinVar variants
20
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MED12L
🧬
Gene-Disease Validity (ClinGen)
Nizon-Isidor syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 541 VUS of 661 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.18LOEUF
pLI 1.000
Z-score 9.13
OE 0.12 (0.08–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.13Z-score
OE missense 0.74 (0.70–0.79)
869 obs / 1170.5 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.0.12 (0.08–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.70–0.79)
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.1.03
0≤1.21.6
LoF obs/exp: 15 / 125.2Missense obs/exp: 869 / 1170.5Syn Z: -0.46

ClinVar Variant Classifications

661 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic16
VUS541
Likely Benign90
Benign6
Conflicting4
4
Pathogenic
16
Likely Pathogenic
541
VUS
90
Likely Benign
6
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
3
0
4
Likely Pathogenic
8
1
7
0
16
VUS
6
517
17
1
541
Likely Benign
0
30
7
53
90
Benign
0
2
2
2
6
Conflicting
—4
Total155503656661

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MED12L · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Nizon-Isidor syndrome

MIM #618872

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Rare MED12L Variants Are Associated with Susceptibility to Guttate Psoriasis in the Han Chinese Population.
Wu K et al.·Dermatology
2024Meta-analysis
Unraveling the genetic susceptibility of irritable bowel syndrome: integrative genome-wide analyses in 845 492 individuals: a diagnostic study.
Huang W et al.·Int J Surg
2025Meta-analysis
Genetic, Clinical and Neuroradiological Spectrum of MED-Related Disorders: An Updated Review.
Fazio A et al.·Genes (Basel)
2025Review
Case Series of Nizon-Isidor Syndrome by Heterozygous Variants in MED12L With Further Evidence of Mitotic Instability in One Case With Diploid-Triploid Mosaicism.
Stewart R et al.·Am J Med Genet A
2026Case report
A Novel Prognostic Risk-Scoring Model Based on RAS Gene-Associated Cluster in Pediatric Acute Myeloid Leukemia.
Luo CJ et al.·Cancer Med
2025Functional
DNA methylation signatures associated with prognosis of gastric cancer.
Dai J et al.·BMC Cancer
2021
Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines.
Brown CC et al.·Pharmacogenomics
2014
Two epilepsy-associated variants in KCNA2 (K(V) 1.2) at position H310 oppositely affect channel functional expression.
Mínguez-Viñas T et al.·J Physiol
2023Functional
De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
Calpena E et al.·Am J Hum Genet
2019
Functional characterization of the MED12 p.Arg1138Trp variant in females: implications for neural development and disease mechanism.
Shaw NC et al.·Mol Med
2025Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools