MED15

Summary

MED15 (mediator complex subunit 15, HGNC:14248) is a protein-coding gene on chromosome 22q11.21, encoding Mediator of RNA polymerase II transcription subunit 15 (Q96RN5). 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: 15.2% of cell lines).

The protein encoded by this gene is a subunit of the multiprotein complexes PC2 and ARC/DRIP and may function as a transcriptional coactivator in RNA polymerase II transcription. This gene contains stretches of trinucleotide repeats and is located in the chromosome 22 region which is deleted in DiGeorge syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51586 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 116 total — 1 pathogenic
• Cancer dependency (DepMap): dependent in 15.2% of screened cell lines
• MANE Select transcript: NM_001003891

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14248
Approved symbol	MED15
Name	mediator complex subunit 15
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	TIG-1, CAG7A, Arc105
Ensembl gene	ENSG00000099917
Ensembl biotype	protein_coding
OMIM	607372
Entrez	51586

Gene structure

Transcript identifiers

Ensembl transcripts: 59 — 42 protein_coding, 9 retained_intron, 4 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000263205, ENST00000292733, ENST00000382974, ENST00000406969, ENST00000414658, ENST00000420849, ENST00000423862, ENST00000424287, ENST00000428629, ENST00000432052, ENST00000433831, ENST00000436496, ENST00000438962, ENST00000441501, ENST00000444094, ENST00000445189, ENST00000445987, ENST00000451058, ENST00000457322, ENST00000461076, ENST00000473028, ENST00000473244, ENST00000476187, ENST00000476767, ENST00000477824, ENST00000478831, ENST00000486656, ENST00000487550, ENST00000489651, ENST00000492381, ENST00000493216, ENST00000853210, ENST00000853211, ENST00000853212, ENST00000853213, ENST00000853214, ENST00000853215, ENST00000853216, ENST00000853217, ENST00000853218, ENST00000853219, ENST00000853220, ENST00000853221, ENST00000853222, ENST00000853223, ENST00000853224, ENST00000853225, ENST00000853226, ENST00000912866, ENST00000912867, ENST00000912868, ENST00000912869, ENST00000912870, ENST00000954415, ENST00000954416, ENST00000954417, ENST00000954418, ENST00000954419, ENST00000954420

RefSeq mRNA: 6 — MANE Select: NM_001003891 NM_001003891, NM_001293234, NM_001293235, NM_001293236, NM_001293237, NM_015889

CCDS: CCDS13781, CCDS33602, CCDS74824, CCDS77653

Canonical transcript exons

ENST00000263205 — 18 exons

Exon	Start	End
ENSE00001309980	20575113	20575232
ENSE00001871169	20507610	20507746
ENSE00003479224	20585728	20585826
ENSE00003483235	20537117	20537204
ENSE00003543591	20584359	20584425
ENSE00003544921	20564450	20564688
ENSE00003550695	20585101	20585267
ENSE00003560468	20583113	20583247
ENSE00003569829	20582611	20582747
ENSE00003575247	20582840	20582967
ENSE00003576775	20586568	20587619
ENSE00003630542	20584855	20585015
ENSE00003640362	20566467	20566817
ENSE00003652421	20583330	20583393
ENSE00003656976	20551436	20551487
ENSE00003659259	20568521	20568631
ENSE00003670601	20553145	20553174
ENSE00003791446	20554936	20555148

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 98.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.4718 / max 428.3990, expressed in 1827 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191128	56.6406	1827
191126	2.7755	1289
191125	1.8519	882
191130	1.4570	654
191139	0.9956	116
191127	0.8022	268
191129	0.7924	506
191142	0.7647	299
209398	0.5385	288
191143	0.3517	91

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.18	gold quality
granulocyte	CL:0000094	97.31	gold quality
peripheral nervous system	UBERON:0000010	95.72	gold quality
tibial nerve	UBERON:0001323	95.72	gold quality
left adrenal gland	UBERON:0001234	95.59	gold quality
right adrenal gland	UBERON:0001233	95.54	gold quality
left adrenal gland cortex	UBERON:0035825	95.45	gold quality
upper lobe of left lung	UBERON:0008952	95.41	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.38	gold quality
metanephros cortex	UBERON:0010533	95.29	gold quality
popliteal artery	UBERON:0002250	95.28	gold quality
tibial artery	UBERON:0007610	95.28	gold quality
right adrenal gland cortex	UBERON:0035827	95.24	gold quality
body of uterus	UBERON:0009853	95.23	gold quality
adrenal cortex	UBERON:0001235	95.12	gold quality
right coronary artery	UBERON:0001625	95.12	gold quality
skin of leg	UBERON:0001511	95.09	gold quality
stromal cell of endometrium	CL:0002255	95.05	gold quality
lower esophagus mucosa	UBERON:0035834	95.04	gold quality
right uterine tube	UBERON:0001302	94.98	gold quality
spleen	UBERON:0002106	94.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.97	gold quality
aorta	UBERON:0000947	94.92	gold quality
ectocervix	UBERON:0012249	94.86	gold quality
right lung	UBERON:0002167	94.83	gold quality
endocervix	UBERON:0000458	94.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.59	gold quality
lower esophagus	UBERON:0013473	94.58	gold quality
ascending aorta	UBERON:0001496	94.56	gold quality
mucosa of stomach	UBERON:0001199	94.53	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	355.28
E-ANND-3	yes	8.41

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NCF2	Unknown

miRNA regulators (miRDB)

24 targeting MED15, 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-10401-5P	99.99	65.79	948
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-6511A-3P	97.60	66.61	713
HSA-MIR-6511B-3P	97.60	66.61	713
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-3907	96.76	65.04	662
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-4769-5P	95.37	66.09	570

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 15.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• The protein encoded by this gene was identified as ARC105, a 105kDa component of the Activator-Recruited Cofactor (ARC) that is involved in mediating gene activation by several classes of transcriptional regulators. (PMID:10235267)
• Methylation of TIG1 in prostatic neoplasms correlates with methylation of the retinoic acid receptor beta gene. (PMID:14691453)
• Limited role of exon 7 PCQAP polymorphisms in the pathogenesis of schizophrenia. (PMID:15318033)
• TIG1 gene Silencing by promoter hypermethylation is associated with nasopharyngeal carcinoma (PMID:15455391)
• SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes (PMID:16799563)
• results suggest that TRIM11, with the ubiquitin-proteasome pathway, regulates ARC105 function in TGFbeta signaling (PMID:16904669)
• The data identify PC2 as a novel PLAGL2-binding protein and important mediator of PLAGL2 transactivation. (PMID:20025940)
• MED15 and PUM1 proteins with coiled-coil domains are potent enhancers of polyQ-mediated ataxin-1 protein misfolding and proteotoxicity in vitro and in vivo. (PMID:22916034)
• these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model. (PMID:24374838)
• MED15 overexpression is a clonal event during head and neck squamous cell carcinoma progression. (PMID:25791637)
• MED15 is differentially expressed in tumor-free testis and testicular germ cell tumors (PMID:26377566)
• MED15 as a potential biomarker for head and neck squamous cell carcinoma (PMID:26457685)
• MED15 overexpression arises during androgen deprivation therapy via hyper-activation of PI3K/Akt/mTOR signaling pathway in prostate cancer cells. (PMID:27974704)
• MED15 does seem to play a tumour promoting role in the progression and metastatic spread of renal cell carcinoma (PMID:29400661)
• In this article, we described MED15-TFE3 renal cell carcinoma (RCC), a rare gene subtype of Xp11 translocation RCCs, that was confirmed by FISH and RNA sequencing. The tumor demonstrated different morphological features and immunophenotypic characteristics with the cases reported in literatures, expanding our understanding on heterogeneity of MED15-TFE3 RCC. (PMID:31828108)
• MED15, transforming growth factor beta 1 (TGF-beta1), FcgammaRIII (CD16), and HNK-1 (CD57) are prognostic biomarkers of oral squamous cell carcinoma. (PMID:32439976)
• MED15 prion-like domain forms a coiled-coil responsible for its amyloid conversion and propagation. (PMID:33772081)
• Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator. (PMID:33904398)
• Cystic MED15::TFE3 translocation renal cell carcinoma: histologic mimicker of multilocular cystic renal neoplasm of low malignant potential with review of the literature. (PMID:36997032)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	med15	ENSDARG00000014292
mus_musculus	Med15	ENSMUSG00000012114
rattus_norvegicus	Med15	ENSRNOG00000001877
drosophila_melanogaster	MED15	FBGN0027592

Protein

Protein identifiers

Mediator of RNA polymerase II transcription subunit 15 — Q96RN5 (reviewed: Q96RN5)

Alternative names: Activator-recruited cofactor 105 kDa component, CTG repeat protein 7a, Mediator complex subunit 15, Positive cofactor 2 glutamine/Q-rich-associated protein, TPA-inducible gene 1 protein, Trinucleotide repeat-containing gene 7 protein

All UniProt accessions (16): Q96RN5, C9J1I1, C9JCQ3, C9JEM1, C9JGN2, C9JJ12, C9JLN7, C9JM58, C9JWK5, C9JZV5, F2Z2B7, F8WCS1, F8WDM6, F8WEJ4, G3V1P5, H7C308

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 preinitiation complex with RNA polymerase II and the general transcription factors. Required for cholesterol-dependent gene regulation. Positively regulates the Nodal 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. Interacts with SMAD2, SMAD3, SREBF1 and SREBF2. Interacts with WWTR1. Interacts with TRIM11.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in all tissues examined, including heart, brain, lung, spleen, thymus, pancreas, blood leukocyte and placenta. However, the level of expression varied, with highest expression in the placenta and peripheral blood and lowest in the pancreas and kidney.

Post-translational modifications. Ubiquitinated by TRIM11, leading to proteasomal degradation.

Induction. By 12-O-tetradecanoylphorbol-13-acetate (TPA).

Polymorphism. The poly-Gln region from amino acids 235-262 of PCQAP is polymorphic. There are from 15 to 18 repeats in the Italian population.

Similarity. Belongs to the Mediator complex subunit 15 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96RN5-1	1	yes
Q96RN5-2	2
Q96RN5-3	3

RefSeq proteins (6): NP_001003891, NP_001280163, NP_001280164, NP_001280165, NP_001280166, NP_056973 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019087	Med15_N	Domain
IPR036529	KIX_dom_sf	Homologous_superfamily
IPR048385	Med15_central	Domain
IPR048386	Med15_C	Domain

Pfam: PF09606, PF21538, PF21539

UniProt features (59 total): helix 12, sequence conflict 11, compositionally biased region 10, strand 8, region of interest 4, turn 4, mutagenesis site 3, modified residue 2, splice variant 2, chain 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7EMF	ELECTRON MICROSCOPY	3.5
8TRH	ELECTRON MICROSCOPY	3.7
7ENA	ELECTRON MICROSCOPY	4.07
7ENC	ELECTRON MICROSCOPY	4.13
8GXS	ELECTRON MICROSCOPY	4.16
7ENJ	ELECTRON MICROSCOPY	4.4
8T9D	ELECTRON MICROSCOPY	4.66
7LBM	ELECTRON MICROSCOPY	4.8
8GXQ	ELECTRON MICROSCOPY	5.04
8TQW	ELECTRON MICROSCOPY	8.2
2GUT	SOLUTION NMR
8J9A	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RN5-F1	62.26	0.15

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 (2): 349, 603

Mutagenesis-validated functional residues (3):

Position	Phenotype
42	abrogates interaction with srebf1.
58	abrogates interaction with srebf1.
60	abrogates interaction with srebf1.

Function

Pathways and Gene Ontology

Reactome pathways

15 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-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
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-9820952	Respiratory Syncytial Virus Infection Pathway
R-HSA-9824446	Viral Infection Pathways
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 150 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, ONKEN_UVEAL_MELANOMA_UP, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, E4F1_Q6, GOBP_MAINTENANCE_OF_CELL_NUMBER, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, TGANTCA_AP1_C, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, PU1_Q6, CREB_Q3, DOUGLAS_BMI1_TARGETS_UP, GOBP_PROTEIN_DNA_COMPLEX_ORGANIZATION, MODULE_48, MODULE_95

GO Biological Process (5): positive regulation of transcription elongation by RNA polymerase II (GO:0032968), somatic stem cell population maintenance (GO:0035019), RNA polymerase II preinitiation complex assembly (GO:0051123), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (2): transcription coregulator activity (GO:0003712), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), membrane (GO:0016020), core mediator complex (GO:0070847)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
RNA Polymerase II Transcription	1
Adipogenesis	1
Respiratory Syncytial Virus Infection Pathway	1
Metabolism of lipids	1
Metabolism	1
Disease	1
Gene expression (Transcription)	1
Viral Infection Pathways	1
Infectious disease	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of transcription by RNA polymerase II	2
transcription initiation at RNA polymerase II promoter	2
transcription elongation by RNA polymerase II	1
positive regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
stem cell population maintenance	1
transcription preinitiation complex assembly	1
regulation of transcription initiation by RNA polymerase II	1
positive regulation of DNA-templated transcription initiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

1720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MED15	MED23	Q9ULK4	969
MED15	MED14	O60244	964
MED15	MED27	Q6P2C8	962
MED15	MED29	Q9NX70	952
MED15	MED16	Q9Y2X0	948
MED15	MED12	Q93074	916
MED15	MED10	Q9BTT4	911
MED15	MED24	O75448	894
MED15	MED13	Q9UHV7	894
MED15	MED18	Q9BUE0	884
MED15	MED22	Q15528	878
MED15	MED19	A0JLT2	873
MED15	MED17	Q9NVC6	872
MED15	MED7	O43513	851
MED15	CDK8	P49336	849

IntAct

149 interactions, top by confidence:

A	B	Type	Score
CDK8	MED1	psi-mi:“MI:0914”(association)	0.920
CDK8	MED1	psi-mi:“MI:0915”(physical association)	0.920
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED10	MED19	psi-mi:“MI:0915”(physical association)	0.910
CDK8	MED14	psi-mi:“MI:0914”(association)	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
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
MED31	MED19	psi-mi:“MI:0914”(association)	0.840

BioGRID (269): MED15 (Affinity Capture-MS), MED15 (Affinity Capture-MS), MED15 (Affinity Capture-MS), MED15 (Affinity Capture-MS), MED15 (Affinity Capture-MS), MED15 (Two-hybrid), MED15 (Affinity Capture-MS), MED15 (Affinity Capture-MS), MED15 (Affinity Capture-MS), MED15 (Two-hybrid), MED15 (Two-hybrid), MED15 (Affinity Capture-Western), MED1 (Co-fractionation), MED10 (Co-fractionation), MED11 (Co-fractionation)

ESM2 similar proteins: A0A3Q7JC00, A0JM64, A0JNC2, A2VE44, A4IHD9, B2C6R6, B5DE09, B8BCZ8, E7F1H9, F4JT98, O09000, O57539, P78364, Q0WVM7, Q15596, Q17BA4, Q2NLB0, Q3TCX3, Q5RDA3, Q5TP13, Q5ZL54, Q61026, Q64028, Q6GP15, Q6K271, Q6NS15, Q6PEH8, Q71SY5, Q7XYY2, Q7ZVN7, Q80TM6, Q8C7E9, Q8CHY6, Q8HXM1, Q8IZL2, Q8VCB2, Q8W234, Q90WJ3, Q924H2, Q940A7

Diamond homologs: Q17BA4, Q5TP13, Q6NS15, Q7ZVN7, Q924H2, Q96RN5, Q9Y149

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MED15	“form complex”	“Core mediator complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 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	27	72.8×	2e-43
Adipogenesis	30	64.3×	2e-46
RSV-host interactions	27	57.9×	2e-40
Regulation of lipid metabolism by PPARalpha	28	54.1×	5e-41
Transcriptional regulation of white adipocyte differentiation	29	51.5×	9e-42
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	17	50.2×	1e-23
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	17	45.9×	6e-23
PPARA activates gene expression	29	37.5×	2e-37

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	26	97.8×	2e-44
RNA polymerase II preinitiation complex assembly	25	84.9×	4e-41
positive regulation of transcription initiation by RNA polymerase II	25	84.9×	4e-41
transcription initiation at RNA polymerase II promoter	8	37.5×	4e-09
somatic stem cell population maintenance	12	37.2×	5e-14
positive regulation of miRNA transcription	7	25.4×	7e-07
response to estradiol	5	12.4×	2e-03
transcription by RNA polymerase II	12	10.6×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	82
Likely benign	10
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1879568	GRCh37/hg19 22q11.21(chr22:19184000-21416024)x1	Pathogenic

SpliceAI

3103 predictions. Top by Δscore:

Variant	Effect	Δscore
22:20507744:AAT:A	donor_gain	1.0000
22:20507745:AT:A	donor_gain	1.0000
22:20507746:TGTG:T	donor_loss	1.0000
22:20507747:G:GG	donor_gain	1.0000
22:20507747:G:T	donor_loss	1.0000
22:20507749:GAG:G	donor_loss	1.0000
22:20537115:A:AG	acceptor_gain	1.0000
22:20537116:G:GA	acceptor_gain	1.0000
22:20537116:GC:G	acceptor_gain	1.0000
22:20537116:GCGA:G	acceptor_gain	1.0000
22:20537203:GG:G	donor_gain	1.0000
22:20537204:GG:G	donor_gain	1.0000
22:20551488:G:GG	donor_gain	1.0000
22:20551492:G:GG	donor_gain	1.0000
22:20555149:G:GG	donor_gain	1.0000
22:20564446:TCAGC:T	acceptor_loss	1.0000
22:20564448:A:AG	acceptor_gain	1.0000
22:20564448:AG:A	acceptor_loss	1.0000
22:20564449:G:GT	acceptor_gain	1.0000
22:20564449:GC:G	acceptor_gain	1.0000
22:20564449:GCC:G	acceptor_gain	1.0000
22:20564449:GCCC:G	acceptor_gain	1.0000
22:20564449:GCCCA:G	acceptor_gain	1.0000
22:20566465:A:AG	acceptor_gain	1.0000
22:20566466:G:GG	acceptor_gain	1.0000
22:20566818:G:GG	donor_gain	1.0000
22:20568627:TCCAG:T	donor_loss	1.0000
22:20568629:CAGGT:C	donor_loss	1.0000
22:20568631:GGTGA:G	donor_loss	1.0000
22:20568632:G:C	donor_loss	1.0000

AlphaMissense

5177 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:20507706:T:A	W10R	1.000
22:20507706:T:C	W10R	1.000
22:20507708:G:C	W10C	1.000
22:20507708:G:T	W10C	1.000
22:20507725:G:C	R16P	1.000
22:20537172:G:A	E42K	1.000
22:20537182:T:A	V45D	1.000
22:20537194:C:A	A49D	1.000
22:20551442:T:C	Y55H	1.000
22:20551442:T:G	Y55D	1.000
22:20551443:A:G	Y55C	1.000
22:20551446:T:C	L56P	1.000
22:20551452:T:C	L58P	1.000
22:20551458:C:A	A60D	1.000
22:20551461:G:C	R61T	1.000
22:20551461:G:T	R61M	1.000
22:20551464:T:A	L62H	1.000
22:20551464:T:C	L62P	1.000
22:20551472:C:G	H65D	1.000
22:20551476:T:C	F66S	1.000
22:20583169:T:C	Y532H	1.000
22:20583169:T:G	Y532D	1.000
22:20583182:T:C	L536P	1.000
22:20583191:T:A	L539Q	1.000
22:20583191:T:C	L539P	1.000
22:20583191:T:G	L539R	1.000
22:20583193:T:C	S540P	1.000
22:20583199:T:C	Y542H	1.000
22:20583200:A:G	Y542C	1.000
22:20583203:T:A	I543N	1.000

dbSNP variants (sampled 300 via entrez): RS1000017832 (22:20575948 G>A), RS1000020117 (22:20524701 A>C,G), RS1000079152 (22:20543414 G>C), RS1000088313 (22:20569028 G>A), RS1000129895 (22:20543016 GT>G), RS1000212055 (22:20585691 C>G,T), RS1000242005 (22:20530443 G>A), RS1000273188 (22:20521349 G>A,C,T), RS1000291065 (22:20580388 C>T), RS1000305975 (22:20564244 A>T), RS1000357484 (22:20569068 A>G), RS1000379459 (22:20537401 G>A), RS1000423524 (22:20563147 T>A), RS1000489963 (22:20541736 G>A), RS1000576998 (22:20546313 T>C)

Disease associations

OMIM: gene MIM:607372 | disease phenotypes: MIM:142623

GenCC curated gene-disease

Mondo (1): Hirschsprung disease (MONDO:0018309)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006482_26	Lung function (FEV1/FVC)	3.000000e-10
GCST006482_27	Lung function (FEV1/FVC)	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
cobaltous chloride	increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Cisplatin	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Ivermectin	decreases expression	1
Methotrexate	affects response to substance	1
Polycyclic Aromatic Hydrocarbons	increases expression, affects cotreatment, increases abundance	1
Selenium	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Sulindac	increases expression	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Vitamin E	affects cotreatment, increases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT00671684	PHASE1/PHASE2	UNKNOWN	Endoscopic Mucosal Resection (EMR) for Diagnosis of Hirschsprung’s Disease
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03406741	Not specified	COMPLETED	Neuropsychological Development and Functional Outcome Sin Children With Hirschsprung Disease at School Age
NCT03626350	Not specified	ACTIVE_NOT_RECRUITING	Prospective Evaluation of the Efficacy and Safety of Submucosal Endoscopy
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04713085	Not specified	COMPLETED	Sacral Neuromodulation in Children and Adolescents
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies