MED12L

Chr 3AD

mediator complex subunit 12L

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

NCBI Gene: 116931ENSG00000144893UniProt: Q86YW9OMIM: 611318

The protein is a component of the Mediator complex that functions as a coactivator for RNA polymerase II-dependent gene transcription by bridging gene-specific regulatory proteins with the basal transcription machinery. Mutations cause Nizon-Isidor syndrome with autosomal dominant inheritance. This gene is extremely intolerant to loss-of-function variants, indicating that proper protein dosage is critical for normal development.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.181 OMIM phenotype
Clinical Summary— MED12L
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Gene-Disease Validity (ClinGen)
Nizon-Isidor syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.
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ClinVar Variants
13 unique Pathogenic / Likely Pathogenic· 228 VUS of 300 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
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
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
LoF OE0.12 (0.08–0.18)
0≤0.351.4
Missense OE0.74 (0.70–0.79)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 15 / 125.2Missense obs/exp: 869 / 1170.5Syn Z: -0.46
DN
0.2997th %ile
GOF
0.2597th %ile
LOF
0.83top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 77% of P/LP variants are LoF · LOEUF 0.18

Literature Evidence

LOFOverall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect.PMID:31155615

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
Likely Pathogenic11
VUS228
Likely Benign53
Benign3
Conflicting3
2
Pathogenic
11
Likely Pathogenic
228
VUS
53
Likely Benign
3
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
1
0
2
Likely Pathogenic
9
1
1
0
11
VUS
1
218
8
1
228
Likely Benign
0
18
5
30
53
Benign
0
1
0
2
3
Conflicting
—3
Total112381533300

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Correspondence on "Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect" by Nizon et al.
Ferraz MK et al.·Genet Med
2022
Evidence of maternal inheritance of Nizon-Isidor syndrome in an individual with GAMT and TNFRSF13B sequence variants.
Dutta D et al.·J Hum Genet
2025
Epigenetic regulation of MED12: a key contributor to the leukemic chromatin landscape and transcriptional dysregulation
Chavan A et al.·Epigenetics Chromatin
2025
Effects of exposure to urban particulate matter SRM 1648a during pregnancy on the neurobehavioral development of offspring mice.
Wen Y et al.·Ecotoxicol Environ Saf
2021
The subunit composition of the mammalian Mediator complex is not conserved in all vertebrates: Insights from evolutionary plasticity of fish genomes.
Symonová R et al.·Protein Sci
2026
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
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
Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect.
Nizon M et al.·Genet Med
2019
Mediator kinase module proteins, genetic alterations and expression of super-enhancer regulated genes in colorectal cancer.
Voutsadakis IA·Pharmacol Rep
2024
Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors.
Hesson LB et al.·Mol Cancer Res
2016
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients