MED12

Summary

MED12 (mediator complex subunit 12, HGNC:11957) is a protein-coding gene on chromosome Xq13.1, encoding Mediator of RNA polymerase II transcription subunit 12 (Q93074). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. It is a selective cancer dependency (DepMap: 57.0% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 9968 — RefSeq curated summary.

At a glance

• Gene–disease (curated): MED12-related intellectual disability syndrome (Definitive, ClinGen) — +12 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 4,170 total — 285 pathogenic, 142 likely-pathogenic
• Phenotypes (HPO): 389
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 9 cancer types
• Cancer dependency (DepMap): dependent in 57.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005120

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11957
Approved symbol	MED12
Name	mediator complex subunit 12
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	CAGH45, HOPA, OPA1, TRAP230, KIAA0192, OKS, ARC240, Kto
Ensembl gene	ENSG00000184634
Ensembl biotype	protein_coding
OMIM	300188
Entrez	9968

Gene structure

Transcript identifiers

Ensembl transcripts: 56 — 26 retained_intron, 15 protein_coding, 13 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000333646, ENST00000374080, ENST00000374102, ENST00000429213, ENST00000444034, ENST00000460771, ENST00000462984, ENST00000471663, ENST00000489199, ENST00000685082, ENST00000685182, ENST00000685655, ENST00000685789, ENST00000686169, ENST00000686548, ENST00000687161, ENST00000687382, ENST00000687542, ENST00000687701, ENST00000687973, ENST00000688079, ENST00000688231, ENST00000688508, ENST00000688622, ENST00000688663, ENST00000688718, ENST00000688774, ENST00000688881, ENST00000688993, ENST00000689008, ENST00000689489, ENST00000689768, ENST00000690145, ENST00000690242, ENST00000690250, ENST00000690523, ENST00000690690, ENST00000690807, ENST00000690828, ENST00000690878, ENST00000691113, ENST00000691283, ENST00000691385, ENST00000691426, ENST00000691468, ENST00000691909, ENST00000692304, ENST00000692864, ENST00000692893, ENST00000692964, ENST00000693050, ENST00000693182, ENST00000693324, ENST00000693391, ENST00000938012, ENST00000938013

RefSeq mRNA: 1 — MANE Select: NM_005120 NM_005120

CCDS: CCDS43970

Canonical transcript exons

ENST00000374080 — 45 exons

Exon	Start	End
ENSE00001292242	71125351	71125495
ENSE00001293489	71124764	71124844
ENSE00001294136	71129114	71129215
ENSE00001294617	71123594	71123720
ENSE00001295156	71121562	71121816
ENSE00001296518	71122738	71122874
ENSE00001296976	71127336	71127467
ENSE00001300478	71132377	71132538
ENSE00001301847	71141230	71141370
ENSE00001302726	71129680	71129855
ENSE00001304220	71122508	71122607
ENSE00001306503	71120971	71121152
ENSE00001308653	71127893	71128120
ENSE00001308964	71133123	71133212
ENSE00001310359	71124976	71125146
ENSE00001310936	71126036	71126154
ENSE00001311649	71131550	71131621
ENSE00001312401	71128598	71128718
ENSE00001314036	71123095	71123226
ENSE00001315494	71141883	71141964
ENSE00001316415	71134713	71134848
ENSE00001317469	71122200	71122346
ENSE00001318901	71121327	71121437
ENSE00001319521	71140635	71140857
ENSE00001320087	71125663	71125713
ENSE00001321773	71124159	71124388
ENSE00001322710	71132845	71132956
ENSE00001325903	71130035	71130214
ENSE00001326693	71128296	71128440
ENSE00001326884	71134357	71134466
ENSE00001329624	71126341	71126484
ENSE00001330088	71132073	71132206
ENSE00001462506	71136281	71136655
ENSE00001462511	71135092	71135253
ENSE00001866889	71142175	71142450
ENSE00001947797	71118596	71118853
ENSE00003492088	71137558	71137635
ENSE00003497358	71126969	71127132
ENSE00003545190	71137726	71137943
ENSE00003545544	71129316	71129429
ENSE00003673387	71137187	71137383
ENSE00003674007	71136879	71137029
ENSE00003716243	71119686	71119877
ENSE00003716683	71119373	71119477
ENSE00003748265	71120014	71120170

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 95.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3890 / max 185.4748, expressed in 1803 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196653	8.3973	1776
196652	4.9752	1540
196654	1.0165	656

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	95.25	gold quality
right adrenal gland	UBERON:0001233	94.95	gold quality
left ovary	UBERON:0002119	94.35	gold quality
right ovary	UBERON:0002118	94.24	gold quality
left adrenal gland	UBERON:0001234	94.12	gold quality
left adrenal gland cortex	UBERON:0035825	94.02	gold quality
adrenal cortex	UBERON:0001235	93.95	gold quality
adrenal tissue	UBERON:0018303	93.79	gold quality
adrenal gland	UBERON:0002369	93.55	gold quality
body of uterus	UBERON:0009853	93.37	gold quality
right uterine tube	UBERON:0001302	93.33	gold quality
spleen	UBERON:0002106	92.50	gold quality
endocervix	UBERON:0000458	92.33	gold quality
right lobe of thyroid gland	UBERON:0001119	92.28	gold quality
granulocyte	CL:0000094	92.23	gold quality
left lobe of thyroid gland	UBERON:0001120	92.03	gold quality
tibial nerve	UBERON:0001323	91.87	gold quality
thyroid gland	UBERON:0002046	91.26	gold quality
ventricular zone	UBERON:0003053	91.22	gold quality
ganglionic eminence	UBERON:0004023	91.00	gold quality
ovary	UBERON:0000992	90.79	gold quality
adenohypophysis	UBERON:0002196	90.79	gold quality
metanephros cortex	UBERON:0010533	90.56	gold quality
pituitary gland	UBERON:0000007	90.45	gold quality
omental fat pad	UBERON:0010414	90.42	gold quality
peritoneum	UBERON:0002358	90.40	gold quality
stromal cell of endometrium	CL:0002255	90.38	gold quality
ectocervix	UBERON:0012249	90.33	gold quality
mucosa of stomach	UBERON:0001199	90.31	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.25	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.03

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOXP3

Upstream regulators (CollecTRI, top): GLI3

miRNA regulators (miRDB)

38 targeting MED12, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-548AS-3P	99.12	69.12	2294

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 57.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• It is unlikely that the 12 bp duplication variant has relevance to the susceptibility to different subtypes of autism. (PMID:11840515)
• The TRAP230 subunit of TRAP/Mediator was shown to interact directly with RTA. (PMID:12612078)
• The HOPA12bp polymorphism is a significant risk factor for schizophrenia for both men and women. (PMID:16538184)
• the MED12 interface within Mediator is a new component in the Wnt/beta-catenin pathway (PMID:16565090)
• reveal a regulatory role of motionless/Med12 in vertebrate neuronal development (PMID:17088561)
• the HOPA(12bp) allele is a risk factor for schizophrenia in subjects of European ancestry (PMID:17299734)
• Recurrent mutation (2881C>T, leading to R961W) in MED12 located at Xq13, linked to Opitz-Kaveggia syndrome. (PMID:17334363)
• The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. (PMID:17369503)
• Review concludes that a thorough understanding of MED12’s role in transcriptional regulation could have significant benefits for human healthcare. (PMID:17716226)
• These findings implicate Mediator in epigenetic restriction of neuronal gene expression to the nervous system and suggest a pathologic basis for MED12-associated X-linked mental retardation involving impaired REST-dependent neuronal gene regulation. (PMID:18691967)
• Males with this MED12 mutation had deficits in communication skills compared to their socialization and daily living skills. (PMID:18973276)
• Med12–but not Med13–is essential for activating the CDK8 kinase. (PMID:19047373)
• Med12 and Med13 are critical for subcomplex-dependent repression, whereas CDK8 kinase activity is not (PMID:19240132)
• report on a new family with three Opitz-Kaveggia syndrome affected cousins, in which we identified a novel MED12 mutation (PMID:20507344)
• findings show the APP intracellular domain (AICD) activates transcription by targeting MED12; the AICD binds to MED12/Mediator in vitro and in vivo; results identify the MED12 interface in Mediator as a crucial transducer of AICD transactivation (PMID:21293490)
• identified tumor-specific mutations in MED12 gene in 10 of 18 uterine leiomyomas; also found MED12 altered in 70% of tumors from 80 patients;all mutations resided in exon 2 suggesting aberrant function of this region of MED12 contributes to tumorigenesis (PMID:21868628)
• a major role of MED12 in the genesis of leiomyomas, regardless of ethnicity (PMID:22182697)
• Leiomyomas with MED12 mutations express significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4) than those with HMGA2 rearrangements. (PMID:22223266)
• An association between MED12 mutations and leiomyomas in ethnically and racially diverse American women. (PMID:22428002)
• MED12 mutations play unique roles in the pathogenesis of uterine leiomyomas and mutated MED12 could be therapeutically targeted in uterine leiomyomas. (PMID:22532225)
• MED12 alterations could be implicated in the development of smooth muscle tumor and that its expression could be inhibited in malignant tumors. (PMID:22768200)
• show that the FG/R961W and Lujan/N1007S mutations disrupt the gene-specific association of MED12 with a second Mediator subunit, CDK8 (PMID:23091001)
• Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas. (PMID:23132392)
• Study identifies an unexpected activity of MED12 in regulating transforming growth factor b (TGF-b) receptor signaling, as the major mechanism of drug-resistance induction in cancer. (PMID:23178117)
• These findings indicate that MED12 has oncogenic roles in a broad range of smooth muscle neoplasia, including tumors arising in extrauterine locations. (PMID:23222489)
• MED12 mutations occurring in benign and malignant mammalian smooth muscle tumors. (PMID:23225304)
• Among uterine smooth muscle tumours, MED12 mutations are frequently present in conventional leiomyomas, but are significantly less common in histological variants of leiomyoma and leiomyosarcoma. (PMID:23347103)
• Mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. (PMID:23395478)
• The uterine leiomyoma variants harbored MED12 exon 2 mutations significantly less frequently than common leiomyomas. (PMID:23443020)
• The lack of mediator complex subunit 12 mutations in extrauterine leiomyomas and leiomyosarcomas indicates that these tumors arise through a different pathway (PMID:23517922)
• Smooth muscle neoplasms with benign appearance of the primary and secondary mullerian system share a similar genetic background of MED12 mutation in combination with oestrogen dependency. (PMID:23635816)
• Suggest that the p.L1224F mutation in the MED12 gene plays no role in prostate carcinogenesis or that this alteration is only relevant in a small subgroup of tumours. (PMID:23661306)
• The biological function of MED12 and the relationship between MED12 mutations and diseases. Review. (PMID:23836153)
• MED12 mutation is associated with uterine leiomyomas. (PMID:23913526)
• In a cognitively impaired male from this family, who also presented with tall stature and dysmorphism and did not have the MED12 mutation, a 600-kb duplication at 17p13.3 including the YWHAE gene, was found in a mosaic state (PMID:24039113)
• pelvic and retroperitoneal leiomyomas harbor an increased frequency of MED12 mutations and histologically unremarkable adjacent myometrium can harbor similar MED12 mutations (PMID:24196187)
• MED12 mutations and HMGA2 overexpression are independent genetic events that occur in leiomyomas, and they may act differently in the tumorigenesis of uterine leiomyomas. (PMID:24390224)
• The oncogenic exon 2 mutations in MED12 uncouple Cyclin C-CDK8/19 from core Mediator implicate aberrant CDK8/19 activity in uterine leiomyomagenesis. (PMID:24746821)
• MED12 overexpression is a frequent event in castration-resistant prostate cancer (PMID:24938407)
• These results further emphasize the role of MED12 in uterine leiomyomas, show that exon 1 and exon 2 exert their tumorigenic effect in similar manner, and stress that exon 1 should be included in subsequent MED12 screenings. (PMID:24980722)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	med12	ENSDARG00000103953
mus_musculus	Med12	ENSMUSG00000079487
rattus_norvegicus	Med12	ENSRNOG00000003848
drosophila_melanogaster	kto	FBGN0001324
caenorhabditis_elegans		WBGENE00001081

Paralogs (1): MED12L (ENSG00000144893)

Protein

Protein identifiers

Mediator of RNA polymerase II transcription subunit 12 — Q93074 (reviewed: Q93074)

Alternative names: Activator-recruited cofactor 240 kDa component, CAG repeat protein 45, Mediator complex subunit 12, OPA-containing protein, Thyroid hormone receptor-associated protein complex 230 kDa component, Trinucleotide repeat-containing gene 11 protein

All UniProt accessions (22): Q93074, A0A0A0MR79, A0A8I5KQ51, A0A8I5KQY2, A0A8I5KRJ8, A0A8I5KSA4, A0A8I5KUR0, A0A8I5KVA6, A0A8I5KVC2, A0A8I5KVJ2, A0A8I5KVM1, A0A8I5KW86, A0A8I5KWE2, A0A8I5KWM7, A0A8I5KXK9, A0A8I5QJB1, A0A8I5QJG1, A0A8I5QJK7, A0A8I5QJW8, A0A8I5QKU5, H7C191, H7C274

UniProt curated annotations — full annotation on UniProt →

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 pre-initiation 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.

Subunit / interactions. Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Also interacts with CTNNB1 and GLI3.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Disease relevance. Opitz-Kaveggia syndrome (OKS) [MIM:305450] X-linked disorder characterized by intellectual disability, relative macrocephaly, hypotonia and constipation. The disease is caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, X-linked, syndromic, Lujan-Fryns type (MRXSLF) [MIM:309520] A disorder characterized by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild-to-moderate intellectual disability, behavioral aberrations and dysgenesis of the corpus callosum. The disease is caused by variants affecting the gene represented in this entry. Ohdo syndrome, X-linked (OHDOX) [MIM:300895] A syndrome characterized by intellectual disability, 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. The disease is caused by variants affecting the gene represented in this entry. Hardikar syndrome (HDKR) [MIM:301068] An X-linked dominant, multiple congenital anomaly syndrome characterized by foregut malformations, intestinal malrotation, liver and biliary tract disease, genitourinary abnormalities, facial clefting, and pigmentary retinopathy. Some patients may have congenital cardiac defects or vascular abnormalities, including aortic coarctation and carotid/intracranial aneurysms. Neurodevelopment and cognition is normal. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Mediator complex subunit 12 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q93074-1	1	yes
Q93074-2	2
Q93074-3	3

RefSeq proteins (1): NP_005111* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019035	Mediator_Med12	Domain
IPR021989	Mediator_Med12_catenin-bd	Domain
IPR021990	Mediator_Med12_LCEWAV	Domain
IPR051647	Mediator_comp_sub12	Family

Pfam: PF09497, PF12144, PF12145

UniProt features (53 total): modified residue 14, region of interest 13, compositionally biased region 10, sequence variant 10, sequence conflict 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8TQ2	ELECTRON MICROSCOPY	3.8
8TQC	ELECTRON MICROSCOPY	3.8
8TQW	ELECTRON MICROSCOPY	8.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q93074-F1	65.80	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (14): 80, 166, 635, 665, 698, 700, 1258, 1269, 1798, 1899, 1899, 1910, 1994, 2015

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-9833110	RSV-host interactions
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway
R-HSA-9824446	Viral Infection Pathways
R-HSA-9843745	Adipogenesis
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 1247 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_97, RRAGTTGT_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_POSITIVE_REGULATION_OF_CELL_FATE_COMMITMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT

GO Biological Process (20): neural tube closure (GO:0001843), endoderm development (GO:0007492), heart development (GO:0007507), oligodendrocyte development (GO:0014003), Schwann cell development (GO:0014044), protein ubiquitination (GO:0016567), spinal cord development (GO:0021510), somatic stem cell population maintenance (GO:0035019), post-anal tail morphogenesis (GO:0036342), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic neurocranium morphogenesis (GO:0048702), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), axis elongation involved in somitogenesis (GO:0090245), embryonic brain development (GO:1990403), somitogenesis (GO:0001756), regulation of transcription by RNA polymerase II (GO:0006357), neural tube development (GO:0021915), embryonic organ development (GO:0048568)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), chromatin binding (GO:0003682), transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), beta-catenin binding (GO:0008013), nuclear vitamin D receptor binding (GO:0042809), nuclear thyroid hormone receptor binding (GO:0046966), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), mediator complex (GO:0016592), CKM complex (GO:1990508)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Gene expression (Transcription)	2
Regulation of lipid metabolism by PPARalpha	1
RNA Polymerase II Transcription	1
Adipogenesis	1
Respiratory Syncytial Virus Infection Pathway	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Metabolism of lipids	1
Metabolism	1
Disease	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Viral Infection Pathways	1
Infectious disease	1
Developmental Biology	1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	2
glial cell development	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
chordate embryonic development	2
binding	2
nuclear receptor binding	2
cellular anatomical structure	2
primary neural tube formation	1
tube closure	1
tissue development	1
circulatory system development	1
oligodendrocyte differentiation	1
Schwann cell differentiation	1
protein modification by small protein conjugation	1
central nervous system development	1
anatomical structure development	1
stem cell population maintenance	1
anatomical structure morphogenesis	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
embryonic morphogenesis	1
embryonic cranial skeleton morphogenesis	1
non-canonical Wnt signaling pathway	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of transcription by RNA polymerase II	1
regulation of transcription initiation by RNA polymerase II	1
positive regulation of DNA-templated transcription initiation	1
somitogenesis	1
axis elongation	1
embryonic organ development	1
anterior/posterior pattern specification	1
segmentation	1
anatomical structure formation involved in morphogenesis	1
somite development	1
nervous system development	1
tube development	1
epithelium development	1

Protein interactions and networks

STRING

2736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MED12	CCNC	P24863	999
MED12	CDK8	P49336	999
MED12	MED13	Q9UHV7	998
MED12	CDK19	Q9BWU1	990
MED12	MED13L	Q71F56	977
MED12	MED17	Q9NVC6	976
MED12	MED23	Q9ULK4	945
MED12	MED14	O60244	927
MED12	MED15	Q96RN5	916
MED12	EHMT2	Q96KQ7	889
MED12	MED10	Q9BTT4	862
MED12	MED16	Q9Y2X0	848
MED12	CTNNB1	P35222	846
MED12	MED26	O95402	840
MED12	MED6	O75586	807

IntAct

165 interactions, top by confidence:

A	B	Type	Score
CDK8	CCNC	psi-mi:“MI:0914”(association)	0.980
CCNC	CDK8	psi-mi:“MI:0915”(physical association)	0.980
HIF1A	EP300	psi-mi:“MI:0914”(association)	0.960
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
CDK8	MED14	psi-mi:“MI:0914”(association)	0.900
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
MED10	MED24	psi-mi:“MI:0914”(association)	0.870
MED12	MED4	psi-mi:“MI:0915”(physical association)	0.870

BioGRID (421): MED12 (Affinity Capture-MS), MED12 (Affinity Capture-MS), MED12 (Affinity Capture-MS), MED12 (Affinity Capture-MS), MED12 (Affinity Capture-MS), MED12 (Affinity Capture-MS), MED12 (Affinity Capture-MS), MED12 (Affinity Capture-Western), MED12 (Affinity Capture-MS), EFTUD2 (Co-fractionation), MED12 (Co-fractionation), MED12 (Co-fractionation), MED12 (Co-fractionation), MED12 (Co-fractionation), MED12 (Co-fractionation)

ESM2 similar proteins: A0JP85, A1A5H6, A2AGH6, A5GFY4, A5YKK6, B1AY13, B4KJ11, E9Q8I9, O75448, O94915, O95155, P55824, Q0KK59, Q23658, Q24134, Q2PW47, Q2QCI8, Q4V8B3, Q5F3M0, Q5RCU2, Q5RFA0, Q5TBA9, Q60PC0, Q6GLR7, Q6GYQ0, Q6PI53, Q6ZQ08, Q7ZYV9, Q80TJ1, Q80X82, Q80YV3, Q8BHR2, Q8BL99, Q8IXH7, Q8R0Z2, Q8R1A4, Q922L6, Q92797, Q93074, Q96N67

Diamond homologs: A2AGH6, Q2QCI8, Q5RCU2, Q7YQK8, Q86YW9, Q8BQM9, Q93074, Q9VW47

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GLI3	down-regulates	MED12	binding
MED12	“form complex”	“CKM complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 91 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Respiratory Syncytial Virus Infection Pathway	24	71.6×	1e-37
RSV-host interactions	24	56.9×	3e-35
Adipogenesis	24	56.9×	3e-35
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	17	55.5×	2e-24
Regulation of lipid metabolism by PPARalpha	24	51.3×	4e-34
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	17	50.7×	1e-23
Transcriptional regulation of white adipocyte differentiation	25	49.2×	4e-35
Epigenetic regulation by WDR5-containing histone modifying complexes	18	42.1×	2e-23

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	23	89.9×	8e-38
RNA polymerase II preinitiation complex assembly	22	77.7×	1e-34
positive regulation of transcription initiation by RNA polymerase II	21	74.1×	1e-32
somatic stem cell population maintenance	9	29.0×	4e-09
transcription initiation at RNA polymerase II promoter	5	24.3×	1e-04
protein ubiquitination	12	6.5×	3e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 9 cancer types — ALL, CESC, CLLSLL, GBM, LGGNOS, NBL, PRAD, PROSTATE, UCEC.

Clinical variants and AI predictions

ClinVar

4170 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	285
Likely pathogenic	142
Uncertain significance	1509
Likely benign	1349
Benign	215

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012713	NM_130837.3(OPA1):c.820C>T (p.Gln274Ter)	Pathogenic
1012714	NM_130837.3(OPA1):c.2057_2058del (p.His686fs)	Pathogenic
1074910	NM_130837.3(OPA1):c.832del (p.Leu278fs)	Pathogenic
1074919	NM_130837.3(OPA1):c.2197del (p.Gln733fs)	Pathogenic
1074939	NC_000003.12:g.193645729del	Pathogenic
1176167	NM_130837.3(OPA1):c.2284G>T (p.Glu762Ter)	Pathogenic
1176168	NM_130837.3(OPA1):c.2702dup (p.Leu901fs)	Pathogenic
1184499	NM_130837.3(OPA1):c.3G>A (p.Met1Ile)	Pathogenic
1184972	NM_130837.3(OPA1):c.1359del (p.Leu454fs)	Pathogenic
1210231	NM_005120.3(MED12):c.514G>C (p.Glu172Gln)	Pathogenic
1210232	NM_005120.3(MED12):c.1249-1G>C	Pathogenic
1210246	NM_005120.3(MED12):c.4070G>A (p.Arg1357His)	Pathogenic
1210248	NM_005120.3(MED12):c.4903_4906delinsCCAGCA (p.Val1635fs)	Pathogenic
1210249	NM_005120.3(MED12):c.5111G>A (p.Trp1704Ter)	Pathogenic
1210250	NM_005120.3(MED12):c.5622C>A (p.Tyr1874Ter)	Pathogenic
1210252	NM_005120.3(MED12):c.6169C>T (p.Gln2057Ter)	Pathogenic
1213866	NM_130837.3(OPA1):c.2293A>T (p.Lys765Ter)	Pathogenic
1297583	NM_130837.3(OPA1):c.1948dup (p.Glu650fs)	Pathogenic
1300145	NM_005120.3(MED12):c.2224C>T (p.Gln742Ter)	Pathogenic
1345404	NM_130837.3(OPA1):c.2661G>A (p.Leu887=)	Pathogenic
1367893	NM_130837.3(OPA1):c.2940del (p.Lys981fs)	Pathogenic
1383594	NM_130837.3(OPA1):c.1581del (p.Glu528fs)	Pathogenic
1394309	NM_130837.3(OPA1):c.3003dup (p.Glu1002fs)	Pathogenic
1400268	NM_130837.3(OPA1):c.1149G>A (p.Lys383=)	Pathogenic
1402595	NM_130837.3(OPA1):c.1214_1215dup (p.Thr406fs)	Pathogenic
1422710	NC_000003.11:g.(?193409832)(193409916_?)del	Pathogenic
1424362	NM_130837.3(OPA1):c.2155C>T (p.Gln719Ter)	Pathogenic
1447573	NM_130837.3(OPA1):c.937A>T (p.Arg313Ter)	Pathogenic
1448649	NM_130837.3(OPA1):c.401G>A (p.Trp134Ter)	Pathogenic
1451185	NM_130837.3(OPA1):c.1408A>G (p.Lys470Glu)	Pathogenic

SpliceAI

10906 predictions. Top by Δscore:

Variant	Effect	Δscore
3:193593405:GCCTG:G	donor_gain	1.0000
3:193593408:TGGT:T	donor_loss	1.0000
3:193593409:GGT:G	donor_loss	1.0000
3:193593410:G:C	donor_loss	1.0000
3:193593410:G:GG	donor_gain	1.0000
3:193615670:TTA:T	acceptor_loss	1.0000
3:193615672:A:AG	acceptor_gain	1.0000
3:193615673:G:GA	acceptor_loss	1.0000
3:193615673:G:GG	acceptor_gain	1.0000
3:193615752:GA:G	donor_gain	1.0000
3:193615753:A:AG	donor_gain	1.0000
3:193615753:A:G	donor_gain	1.0000
3:193617172:TTCCA:T	acceptor_loss	1.0000
3:193617173:TCCA:T	acceptor_loss	1.0000
3:193617176:A:AG	acceptor_gain	1.0000
3:193617176:A:T	acceptor_loss	1.0000
3:193617177:G:GA	acceptor_gain	1.0000
3:193617177:G:GC	acceptor_loss	1.0000
3:193617177:GA:G	acceptor_gain	1.0000
3:193617177:GAGA:G	acceptor_gain	1.0000
3:193617177:GAGAA:G	acceptor_gain	1.0000
3:193617283:CAGGT:C	donor_loss	1.0000
3:193617284:AGG:A	donor_loss	1.0000
3:193617285:GGTA:G	donor_loss	1.0000
3:193617287:T:G	donor_loss	1.0000
3:193618865:TAAGG:T	acceptor_loss	1.0000
3:193618866:AAGGT:A	acceptor_loss	1.0000
3:193618867:A:C	acceptor_loss	1.0000
3:193618867:A:G	acceptor_gain	1.0000
3:193618868:G:GC	acceptor_loss	1.0000

AlphaMissense

14265 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:71118835:G:C	Q27H	1.000
X:71118835:G:T	Q27H	1.000
X:71118847:G:C	Q31H	1.000
X:71118847:G:T	Q31H	1.000
X:71119373:G:C	D34H	1.000
X:71119380:T:A	L36Q	1.000
X:71119380:T:C	L36P	1.000
X:71119403:G:C	G44R	1.000
X:71119406:T:C	F45L	1.000
X:71119407:T:C	F45S	1.000
X:71119408:C:A	F45L	1.000
X:71119408:C:G	F45L	1.000
X:71119827:T:A	W116R	1.000
X:71119827:T:C	W116R	1.000
X:71120018:C:A	P134H	1.000
X:71120089:T:A	W158R	1.000
X:71120089:T:C	W158R	1.000
X:71121802:A:C	S363R	1.000
X:71121804:C:A	S363R	1.000
X:71121804:C:G	S363R	1.000
X:71122279:T:C	L394P	1.000
X:71122309:T:C	L404P	1.000
X:71122574:T:A	W439R	1.000
X:71122574:T:C	W439R	1.000
X:71122576:G:C	W439C	1.000
X:71122576:G:T	W439C	1.000
X:71122777:T:C	L463P	1.000
X:71123137:T:A	W510R	1.000
X:71123137:T:C	W510R	1.000
X:71123139:G:C	W510C	1.000

dbSNP variants (sampled 300 via entrez): RS1000044957 (X:71138437 C>G), RS1000204219 (X:71141550 A>G), RS1000652190 (X:71119114 G>A), RS1000684708 (X:71119637 A>T), RS1000702031 (X:71139315 A>G), RS1000933391 (X:71130352 G>A,T), RS1000959167 (X:71123509 A>G), RS1001013256 (X:71124013 TGG>T), RS1001050248 (X:71140856 G>A), RS1001294498 (X:71120496 T>C), RS1001346525 (X:71121311 C>T), RS1001428288 (X:71139346 C>A,T), RS1001762438 (X:71140785 G>A), RS1001775782 (X:71128991 A>G), RS1001882198 (X:71120322 T>C)

Disease associations

OMIM: gene MIM:300188 | disease phenotypes: MIM:305450, MIM:607086, MIM:309520, MIM:165500, MIM:207500, MIM:301800, MIM:217990, MIM:300895, MIM:125250, MIM:616896, MIM:301068, MIM:612726, MIM:610805, MIM:611878, MIM:210000, MIM:606657, MIM:248200, MIM:120970, MIM:268000, MIM:609129, MIM:621481, MIM:258501, MIM:160150, MIM:166710, MIM:194070, MIM:312870, MIM:150699

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant optic atrophy, classic form	Definitive	Autosomal dominant
FG syndrome 1	Definitive	X-linked
X-linked intellectual disability with marfanoid habitus	Definitive	X-linked
optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	Definitive	Autosomal dominant
optic atrophy	Definitive	Autosomal dominant
mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type)	Strong	Autosomal recessive
blepharophimosis - intellectual disability syndrome, MKB type	Strong	X-linked
cholestasis-pigmentary retinopathy-cleft palate syndrome	Strong	X-linked
Behr syndrome	Strong	Autosomal recessive
MED12-related intellectual disability syndrome	Strong	X-linked
OPA1-related optic atrophy with or without extraocular features	Strong	Semidominant
autosomal dominant optic atrophy plus syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
MED12-related intellectual disability syndrome	Definitive	XL
OPA1-related optic atrophy with or without extraocular features	Definitive	SD

Mondo (45): FG syndrome (MONDO:0002010), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), FG syndrome 1 (MONDO:0010590), optic atrophy (MONDO:0003608), X-linked intellectual disability with marfanoid habitus (MONDO:0010655), autosomal dominant optic atrophy, classic form (MONDO:0008134), inherited retinal dystrophy (MONDO:0019118), intellectual disability (MONDO:0001071), imperforate anus (MONDO:0001046), corpus callosum, agenesis of (MONDO:0009022), blepharophimosis - intellectual disability syndrome, MKB type (MONDO:0010477), optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (MONDO:0007429), mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type) (MONDO:0014820), cholestasis-pigmentary retinopathy-cleft palate syndrome (MONDO:0012997), MED12-related intellectual disability syndrome (MONDO:0100000)

Orphanet (28): Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), FG syndrome type 1 (Orphanet:93932), Lujan-Fryns syndrome (Orphanet:776), Autosomal dominant optic atrophy, classic form (Orphanet:98673), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Isolated corpus callosum agenesis (Orphanet:200), Blepharophimosis-intellectual disability syndrome, MKB type (Orphanet:293707), Non-syndromic anorectal malformation (Orphanet:557), Hardikar syndrome (Orphanet:1415), Renal or urinary tract malformation (Orphanet:93545), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260), Behr syndrome (Orphanet:1239), Stargardt disease (Orphanet:827), Autosomal dominant optic atrophy (Orphanet:98672)

HPO phenotypes

389 total (30 of 389 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000049	Shawl scrotum
HP:0000053	Macroorchidism
HP:0000054	Micropenis
HP:0000072	Hydroureter
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000098	Tall stature
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000148	Vaginal atresia
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000185	Cleft soft palate
HP:0000189	Narrow palate
HP:0000194	Open mouth
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST004203_2	Diastolic blood pressure	2.000000e-08
GCST004797_3	Brain volume in infants (grey matter)	1.000000e-07
GCST004860_110	Alcoholic chronic pancreatitis	5.000000e-06
GCST006041_18	Major depressive disorder	6.000000e-08
GCST007297_13	Psychological distress	6.000000e-06
GCST008295_24	Number of decayed, missing and filled tooth surfaces or use of dentures	2.000000e-09
GCST008306_35	Dentures	1.000000e-09
GCST009158_36	Uterine fibroids	2.000000e-18
GCST90002385_592	High light scatter reticulocyte count	3.000000e-76
GCST90002386_503	High light scatter reticulocyte percentage of red cells	1.000000e-79
GCST90002387_185	Immature fraction of reticulocytes	1.000000e-42
GCST90002405_431	Reticulocyte count	6.000000e-64
GCST90002406_582	Reticulocyte fraction of red cells	6.000000e-70

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0008368	infant grey matter volume measurement
EFO:0007006	depressive symptom measurement
EFO:0010078	dentures
EFO:0007986	reticulocyte count

MeSH disease descriptors (26)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D001006	Anus, Imperforate	C06.198.050; C16.131.314.094
D001763	Blepharoptosis	C11.338.204
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D005234	Fatty Liver	C06.552.241
D005909	Glioblastoma	C04.557.465.625.600.380.080.335; C04.557.470.670.380.080.335; C04.557.580.625.600.380.080.335
D006394	Hemangiosarcoma	C04.557.450.795.390; C04.557.645.390
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D029241	Optic Atrophy, Autosomal Dominant	C10.292.700.225.500.100; C10.574.500.662.100; C11.270.564.100; C11.640.451.451.100; C16.320.290.564.100; C16.320.400.630.100; C18.452.660.665
D009901	Optic Nerve Diseases	C10.292.700; C11.640
D010024	Osteoporosis	C05.116.198.579; C18.452.104.579
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
D009396	Wilms Tumor	C04.557.435.595; C04.588.945.947.535.585; C04.700.900; C12.050.351.937.820.535.585; C12.050.351.968.419.473.585; C12.200.758.820.750.585; C12.200.777.419.473.585; C12.900.820.535.585; C12.950.419.473.585; C12.950.983.535.585; C16.320.700.900
C538268	Auditory neuropathy (supp.)
C537669	Behr syndrome (supp.)
C566906	Cakut (supp.)
C567507	Cardiomyopathy, Dilated, 1y (supp.)
C535311	Costeff optic atrophy syndrome (supp.)
C535632	Hardikar syndrome (supp.)
C537724	Lujan Fryns syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724623 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.89	IC50	130	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178532: Inhibition of MED12 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.1300	uM

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
Air Pollutants	increases expression, affects expression, increases abundance	2
Benzo(a)pyrene	increases mutagenesis, increases methylation	2
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
picoxystrobin	decreases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Ozone	affects expression, increases abundance	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Gold Compounds	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697262	Binding	Inhibition of MED12 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

11 cell lines: 5 cancer cell line, 3 embryonic stem cell, 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4B6	SEES3-1V human MED12, clone1	Embryonic stem cell	Male
CVCL_A4B7	SEES3-1V human MED12, clone2	Embryonic stem cell	Male
CVCL_A4B8	SEES3-1V human MED12, clone3	Embryonic stem cell	Male
CVCL_B7GV	MPT-S1	Cancer cell line	Female
CVCL_B8KA	Abcam HCT 116 MED12 KO	Cancer cell line	Male
CVCL_B8YR	Abcam MCF-7 MED12 KO	Cancer cell line	Female
CVCL_B9MJ	Abcam A-549 MED12 KO	Cancer cell line	Male
CVCL_D6PR	KMUGMCi010-A	Induced pluripotent stem cell	Male
CVCL_D6PS	KMUGMCi009-A	Induced pluripotent stem cell	Male
CVCL_M976	T243	Cancer cell line	Male

Clinical trials (associated diseases)

269 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06461286	PHASE1	ACTIVE_NOT_RECRUITING	SAD of IVT PYC-001 in OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy (Sundew)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06970106	PHASE1/PHASE2	RECRUITING	Safety of Single and Repeat Dose of PYC-001 Eye Injections in People With Autosomal Dominant Optic Atrophy (Myrtle)
NCT06140329	Not specified	TERMINATED	Natural History of Autosomal Dominant Optic Atrophy (ADOA), Caused by OPA1 Mutation
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01834079	PHASE1/PHASE2	UNKNOWN	Study the Safety and Efficacy of Bone Marrow Derived Autologous Cells for the Treatment of Optic Nerve Disease
NCT04680143	PHASE1/PHASE2	COMPLETED	Systemic Erythropoietin Injection in Patients Having Optic Atrophy
NCT03011541	Not specified	RECRUITING	Stem Cell Ophthalmology Treatment Study II
NCT04580979	Not specified	COMPLETED	Natural History Study of FDXR Mutation-related Mitochondriopathy
NCT04594590	Not specified	COMPLETED	Natural History Study of SLC25A46 Mutation-related Mitochondriopathy
NCT04723160	Not specified	COMPLETED	Computer Aided Diagnosis of Multiple Eye Fundus Diseases From Color Fundus Photograph
NCT06390579	Not specified	COMPLETED	Building Research With Artificial Intelligence in Neuro-Ophthalmology
NCT03440697	Not specified	ACTIVE_NOT_RECRUITING	Pathogenetic Basis of Aortopathy and Aortic Valve Disease
NCT06783803	Not specified	ACTIVE_NOT_RECRUITING	Application of Linkage Analysis in the Identification of Novel Hereditary Factors in Familial Aneurysms
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10