THBS4

Summary

THBS4 (thrombospondin 4, HGNC:11788) is a protein-coding gene on chromosome 5q14.1, encoding Thrombospondin-4 (P35443). Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions and is involved in various processes including cellular proliferation, migration, adhesion and attachment, inflammatory response to CNS injury, regulation of vascular inflammation and adaptive respo….

The protein encoded by this gene belongs to the thrombospondin protein family. Thrombospondin family members are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. This protein forms a pentamer and can bind to heparin and calcium. It is involved in local signaling in the developing and adult nervous system, and it contributes to spinal sensitization and neuropathic pain states. This gene is activated during the stromal response to invasive breast cancer. It may also play a role in inflammatory responses in Alzheimer’s disease. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7060 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 119 total
• MANE Select transcript: NM_003248

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11788
Approved symbol	THBS4
Name	thrombospondin 4
Location	5q14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113296
Ensembl biotype	protein_coding
OMIM	600715
Entrez	7060

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000350881, ENST00000504720, ENST00000510218, ENST00000511733, ENST00000511888, ENST00000513310, ENST00000515510, ENST00000854343, ENST00000854344, ENST00000970348, ENST00000970349

RefSeq mRNA: 4 — MANE Select: NM_003248 NM_001306212, NM_001306213, NM_001306214, NM_003248

CCDS: CCDS4049, CCDS78027

Canonical transcript exons

ENST00000350881 — 22 exons

Exon	Start	End
ENSE00000756488	80058206	80058314
ENSE00000756491	80058708	80058790
ENSE00000756494	80059440	80059491
ENSE00000756497	80059703	80059905
ENSE00000756500	80061695	80061832
ENSE00000756502	80065409	80065477
ENSE00000756504	80067973	80068125
ENSE00000756506	80070306	80070410
ENSE00000756509	80070643	80070750
ENSE00000756511	80071021	80071180
ENSE00000756513	80072278	80072396
ENSE00000756516	80073275	80073327
ENSE00000756518	80076855	80077048
ENSE00000971700	80055785	80056032
ENSE00000971701	80078049	80078227
ENSE00001368518	80035348	80035625
ENSE00001641112	80078921	80078969
ENSE00003493379	80082406	80082545
ENSE00003494272	80083080	80083287
ENSE00003629712	80079905	80080077
ENSE00003640813	80040077	80040280
ENSE00003646805	80079062	80079258

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 99.92.

FANTOM5 (CAGE): breadth broad, TPM avg 6.8776 / max 627.0018, expressed in 612 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57286	3.9538	253
57287	1.4727	262
57284	1.0287	480
57285	0.4224	153

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.92	gold quality
tendon	UBERON:0000043	99.80	gold quality
tendon of biceps brachii	UBERON:0008188	99.79	gold quality
synovial joint	UBERON:0002217	99.77	gold quality
pericardium	UBERON:0002407	99.12	gold quality
layer of synovial tissue	UBERON:0007616	99.07	gold quality
gluteal muscle	UBERON:0002000	98.47	gold quality
apex of heart	UBERON:0002098	98.40	gold quality
tibial nerve	UBERON:0001323	98.18	gold quality
body of tongue	UBERON:0011876	97.53	gold quality
vena cava	UBERON:0004087	97.38	gold quality
secondary oocyte	CL:0000655	97.35	gold quality
cartilage tissue	UBERON:0002418	97.35	gold quality
urethra	UBERON:0000057	97.13	gold quality
oocyte	CL:0000023	96.81	gold quality
triceps brachii	UBERON:0001509	96.68	gold quality
heart left ventricle	UBERON:0002084	96.12	gold quality
cardiac ventricle	UBERON:0002082	96.04	gold quality
diaphragm	UBERON:0001103	94.76	gold quality
adenohypophysis	UBERON:0002196	94.62	gold quality
pituitary gland	UBERON:0000007	94.30	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.14	gold quality
tongue	UBERON:0001723	93.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.83	gold quality
muscle of leg	UBERON:0001383	93.79	gold quality
smooth muscle tissue	UBERON:0001135	93.73	gold quality
minor salivary gland	UBERON:0001830	93.67	gold quality
gastrocnemius	UBERON:0001388	93.44	gold quality
muscle organ	UBERON:0001630	93.05	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

18 targeting THBS4, 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-3064-3P	100.00	70.09	1254
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-3940-5P	99.14	65.26	493
HSA-MIR-4507	99.14	65.27	515
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-218-2-3P	98.08	67.21	601
HSA-MIR-4670-3P	97.37	68.35	1378
HSA-MIR-424-3P	97.20	65.86	385
HSA-MIR-584-5P	95.82	68.05	848
HSA-MIR-758-5P	93.99	64.46	534

Literature-anchored findings (GeneRIF, showing 35)

• thrombospondin-4 C-terminal peptide has a role in stimulating erythroid cell proliferation (PMID:15474480)
• Promoter hypermethylation of thrombospondin 4 is associated with cutaneous T-cell lymphoma (PMID:15897551)
• A387P in thrombospondin-4 and N700S in thrombospondin-1 polymorphisms perturb calcium binding sites (PMID:16148025)
• biophysical analysis of roles of signature domains of thrombospondin-4 and thrombospondin-2 in calcium binding, fine structure, and inter-modular interactions (PMID:16246837)
• Homozygosity for thrombospondin-4 1186C (Arg387Pro) variant is a risk factor for myocardial infarction especially in older women. (PMID:16923428)
• Gene-expression changes in human evolution that involve specific brain regions, including portions of cerebral cortex. (PMID:17182969)
• The meta-analysis included 6388 (TSP-1), 4930 (TSP-2), and 6978 (TSP-4) cases; none of the polymorphisms was found to be linked with the risk of myocardial infarction. (PMID:18178577)
• High THBS4 methylation resulting in inactivation of the gene is associated with colorectal cancer. (PMID:20846368)
• Identify THBS4 as a powerful marker for diffuse-type gastric adenocarcinomas and to provide an initial characterization of its expression in the course of this disease. (PMID:21701537)
• genetic polymorphism predicts cardiovascular risk in postinfarction patients with high HDL cholesterol and C-reactive protein levels (PMID:22011848)
• The results of thid study suggested that injury-induced spinal TSP4 may contribute to spinal presynaptic hypersensitivity and neuropathic pain states. (PMID:22745497)
• the balancing selection target in THBS4 is likely represented by one or more variants that regulate tissue-specific and sex-specific gene expression (PMID:23420636)
• THBS4 expression in breast cancer-associated extracellular matrix contributes to the activated stromal response exhibited during tumour progression (PMID:23942617)
• Tsp4 functions as an ECM scaffold at myotendinous junctions, with potential therapeutic uses in tendon strengthening and repair (PMID:24941943)
• The THBS4 A387P polymorphism was associated with coronary artery disease in American population. (PMID:25976449)
• THBS2 and THBS4 mRNA are overexpressed in gastric cancer in a Southeast Chinese population. (PMID:27160021)
• the present study demonstrates that THBS4 and lncRNA-THBS4-003 serve a significant role in PCa proliferation and migration via the MMP-9 and p38 MAPK signaling pathway. (PMID:27357608)
• Findings indicate that loss of miR-142 results in the over-expression of THBS4, which enhances HCC migration and vascular invasion. (PMID:28177895)
• In this review article, we summarize the properties and functions of TSP-4 and discuss its role in tissue remodeling. (PMID:29138119)
• TSP-4 A387P polymorphism, but not TSP-1 polymorphism, is an independent risk factor for acute myocardial infarction in Egyptians. (PMID:29336258)
• establish a novel molecular mechanism by which miR-148a-3p upregulates Tsp-4 expression in tenocytes to promote angiogenesis by targeting KLF6, which could be helpful for the treatment of tendinopathy in the future (PMID:29807011)
• TGF-b1, by activating both Smad3 and p38, induces TSP-4, which in turn not only presents a positive feedback regulation on the activation of Smad3 and p38, but also essentially mediates TGF-b1-induced hypertrophic scar (HS) formation formation (PMID:30132849)
• In this study the authors have identified a GXKGHR motif on the collagen II helix to bind to COMP, using a recombinantly expressed collagen II peptide library. This binding sequence is conserved throughout evolution and they demonstrate that TSP-4 binds to the same sequence. (PMID:30464261)
• we report that TSP-4 is present in articular cartilage and increases dramatically in OA, where it might contribute to the maintenance of cartilage structure and function. TSP-4 levels in cartilage correlate positively with OA severity and the anchorage of TSP-4 in the matrix seems to be weaker at an early disease stage. (PMID:30669608)
• THBS4 had positive effects on gastric cancer cell proliferation, progression, and metastasis via targeting KLF9. (PMID:30746617)
• In hepatocellular carcinoma patients, high THBS4 expression was associated with shorter overall and disease-free survival compared with low THBS4 expression. (PMID:30802535)
• Thrombospondin-4 increases with the severity of peripheral arterial disease and is associated with diabetes. (PMID:31227875)
• THBS4 is expressed on cancer-associated fibroblasts in the gastric cancer microenvironment. (PMID:31703077)
• THBS4 silencing regulates the cancer stem cell-like properties in prostate cancer via blocking the PI3K/Akt pathway. (PMID:32421868)
• THBS4 promotes HCC progression by regulating ITGB1 via FAK/PI3K/AKT pathway. (PMID:32567740)
• Pathological Significance and Prognostic Roles of Thrombospondin-3, 4 and 5 in Bladder Cancer. (PMID:33910854)
• Spatiotemporal distribution of thrombospondin-4 and -5 in cartilage during endochondral bone formation and repair. (PMID:33971315)
• THBS4/integrin alpha2 axis mediates BM-MSCs to promote angiogenesis in gastric cancer associated with chronic Helicobacter pylori infection. (PMID:34390328)
• Stimulation with THBS4 activates pathways that regulate proliferation, migration and inflammation in primary human keratinocytes. (PMID:36566568)
• The functional analysis of the rat counterpart. (PMID:7490284)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	thbs4b	ENSDARG00000020072
danio_rerio	thbs4a	ENSDARG00000102777
mus_musculus	Thbs4	ENSMUSG00000021702
rattus_norvegicus	Thbs4	ENSRNOG00000012471
drosophila_melanogaster	Tsp	FBGN0031850

Paralogs (5): ISM1 (ENSG00000101230), COMP (ENSG00000105664), THBS1 (ENSG00000137801), THBS3 (ENSG00000169231), THBS2 (ENSG00000186340)

Protein

Protein identifiers

Thrombospondin-4 — P35443 (reviewed: P35443)

All UniProt accessions (2): P35443, E7ES19

UniProt curated annotations — full annotation on UniProt →

Function. Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions and is involved in various processes including cellular proliferation, migration, adhesion and attachment, inflammatory response to CNS injury, regulation of vascular inflammation and adaptive responses of the heart to pressure overload and in myocardial function and remodeling. Binds to structural extracellular matrix (ECM) proteins and modulates the ECM in response to tissue damage, contributing to cardioprotective and adaptive ECM remodeling. Plays a role in ER stress response, via its interaction with the activating transcription factor 6 alpha (ATF6) which produces adaptive ER stress response factors and protects myocardium from pressure overload. May contribute to spinal presynaptic hypersensitivity and neuropathic pain states after peripheral nerve injury. May play a role in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury in a NOTCH1-dependent manner.

Subunit / interactions. Homopentamer; disulfide-linked. Interacts with PTBP3. Interacts with NOTCH1. Interacts (via EGF-like 3; calcium-binding domain) with ATF6 and facilitates its processing, activation and nuclear translocation.

Subcellular location. Endoplasmic reticulum. Sarcoplasmic reticulum. Secreted. Extracellular space. Extracellular matrix.

Similarity. Belongs to the thrombospondin family.

RefSeq proteins (4): NP_001293141, NP_001293142, NP_001293143, NP_003239* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR003367	Thrombospondin_3-like_rpt	Repeat
IPR008859	Thrombospondin_C	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017897	Thrombospondin_3_rpt	Repeat
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024665	TSP/COMP_CC	Domain
IPR028974	TSP_type-3_rpt	Homologous_superfamily
IPR046970	TSP/COMP_CC_sf	Homologous_superfamily
IPR048287	TSPN-like_N	Domain

Pfam: PF00008, PF02412, PF05735, PF11598

UniProt features (54 total): disulfide bond 23, repeat 8, domain 6, sequence variant 5, compositionally biased region 3, sequence conflict 3, glycosylation site 2, signal peptide 1, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35443-F1	84.81	0.56

Functional residue map

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

Disulfide bonds (23): 258, 261, 290–301, 295–310, 313–324, 330–341, 335–350, 353–377, 383–394, 388–403, 406–418, 424–438, 432–448, 450–461, 477–482, 487–507, 523–543, 546–566, 582–602, 605–625 …

Glycosylation sites (2): 612, 941

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-186797	Signaling by PDGF

MSigDB gene sets: 226 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, AAGCAAT_MIR137, GOBP_BEHAVIOR, MCLACHLAN_DENTAL_CARIES_UP, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PHOSPHORYLATION, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOMF_GROWTH_FACTOR_ACTIVITY, CHANDRAN_METASTASIS_DN, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_POSITIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_MULTICELLULAR_ORGANISMAL_RESPONSE_TO_STRESS, GOBP_LEUKOCYTE_CHEMOTAXIS

GO Biological Process (14): positive regulation of endothelial cell proliferation (GO:0001938), response to unfolded protein (GO:0006986), negative regulation of angiogenesis (GO:0016525), regulation of tissue remodeling (GO:0034103), response to endoplasmic reticulum stress (GO:0034976), behavioral response to pain (GO:0048266), tissue remodeling (GO:0048771), positive regulation of peptidyl-tyrosine phosphorylation (GO:0050731), myoblast migration (GO:0051451), positive regulation of cell division (GO:0051781), endothelial cell-cell adhesion (GO:0071603), positive regulation of neutrophil chemotaxis (GO:0090023), cell adhesion (GO:0007155), signal transduction (GO:0007165)

GO Molecular Function (5): integrin binding (GO:0005178), calcium ion binding (GO:0005509), growth factor activity (GO:0008083), heparin binding (GO:0008201), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), sarcoplasmic reticulum (GO:0016529), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
response to topologically incorrect protein	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
tissue remodeling	1
regulation of multicellular organismal process	1
cellular response to stress	1
behavior	1
response to pain	1
multicellular organismal process	1
positive regulation of protein phosphorylation	1
peptidyl-tyrosine phosphorylation	1
regulation of peptidyl-tyrosine phosphorylation	1
muscle cell migration	1
positive regulation of cellular process	1
cell division	1
regulation of cell division	1
epithelial cell-cell adhesion	1
neutrophil chemotaxis	1
positive regulation of granulocyte chemotaxis	1
regulation of neutrophil chemotaxis	1
positive regulation of neutrophil migration	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
metal ion binding	1
receptor ligand activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
binding	1
cellular anatomical structure	1
extracellular matrix	1

Protein interactions and networks

STRING

2377 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THBS4	ATF6	P18850	911
THBS4	COMP	P49747	792
THBS4	POSTN	Q15063	746
THBS4	CXCR2	P25025	708
THBS4	TNMD	Q9H2S6	702
THBS4	COL6A1	P12109	665
THBS4	COL3A1	P02461	652
THBS4	CD47	Q08722	607
THBS4	CD36	P16671	606
THBS4	FN1	P02751	605
THBS4	SCARB2	Q14108	602
THBS4	SCARB1	Q8WTV0	587
THBS4	TCAP	O15273	551
THBS4	CXCL8	P10145	538
THBS4	MYH1	P12882	523

IntAct

7 interactions, top by confidence:

A	B	Type	Score
THBS4	ITGB1	psi-mi:“MI:0915”(physical association)	0.400
Atf6	THBS4	psi-mi:“MI:0915”(physical association)	0.400
THBS3	APBB1	psi-mi:“MI:0914”(association)	0.350
MATN2	CORO1A	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): THBS4 (Affinity Capture-MS), THBS4 (Reconstituted Complex), THBS4 (Affinity Capture-MS), THBS4 (Affinity Capture-MS), THBS4 (Affinity Capture-MS), THBS4 (Affinity Capture-MS), THBS4 (Affinity Capture-MS), THBS4 (Affinity Capture-MS), THBS4 (Affinity Capture-RNA)

ESM2 similar proteins: A0A126GUP6, A0A1S4GMJ4, A0A1S4H5M5, A0A1S4H5S2, A0A1S4HE51, A0A6I8TBG6, A8JUP7, B3A0R6, F5HKX0, G5ECX0, O15393, O16977, P05049, P08001, P08471, P0CV23, P10323, P21997, P23578, P28175, P29293, P31178, P35443, P48038, P49744, P55114, Q05319, Q17800, Q19040, Q21059, Q26422, Q27081, Q3UQ41, Q4QXT9, Q7JLI1, Q7K5M0, Q804X6, Q8I6K0, Q8MZM7, Q93118

Diamond homologs: A0A1D0C023, A2ARV4, B3EWY9, B3NBB6, B4HVU2, B4PD96, B5DFC9, F1RRV3, O08523, O08710, O42182, O73775, O75095, O75197, O75443, O75581, O77469, O88322, O88572, P01130, P01131, P01266, P01267, P04233, P04441, P06882, P07522, P08460, P10247, P10493, P14543, P20063, P23142, P27590, P31226, P35442, P35443, P35444, P35445, P48960

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	96
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3464 predictions. Top by Δscore:

Variant	Effect	Δscore
5:80035624:GG:G	donor_gain	1.0000
5:80035625:GG:G	donor_gain	1.0000
5:80058283:GCAGA:G	donor_gain	1.0000
5:80058286:GA:G	donor_gain	1.0000
5:80058288:G:GG	donor_gain	1.0000
5:80061693:A:AG	acceptor_gain	1.0000
5:80061694:G:GG	acceptor_gain	1.0000
5:80065401:T:TA	acceptor_gain	1.0000
5:80065404:A:AG	acceptor_gain	1.0000
5:80065405:C:G	acceptor_gain	1.0000
5:80065405:CTAGG:C	acceptor_loss	1.0000
5:80065406:TAGGT:T	acceptor_loss	1.0000
5:80065407:A:T	acceptor_loss	1.0000
5:80065408:G:GC	acceptor_loss	1.0000
5:80065473:CTTTG:C	donor_gain	1.0000
5:80065474:TTTG:T	donor_gain	1.0000
5:80065474:TTTGG:T	donor_loss	1.0000
5:80065475:TTG:T	donor_gain	1.0000
5:80065475:TTGG:T	donor_loss	1.0000
5:80065476:TG:T	donor_gain	1.0000
5:80065477:GG:G	donor_gain	1.0000
5:80065478:G:C	donor_loss	1.0000
5:80065478:G:GG	donor_gain	1.0000
5:80065479:TAA:T	donor_loss	1.0000
5:80067968:TGCA:T	acceptor_loss	1.0000
5:80067970:CA:C	acceptor_loss	1.0000
5:80067971:A:AG	acceptor_gain	1.0000
5:80067971:AG:A	acceptor_gain	1.0000
5:80067971:AGG:A	acceptor_gain	1.0000
5:80067972:G:GG	acceptor_gain	1.0000

AlphaMissense

6411 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:80071027:T:A	C523S	1.000
5:80071027:T:C	C523R	1.000
5:80071028:G:C	C523S	1.000
5:80071029:T:G	C523W	1.000
5:80076889:T:A	C643S	1.000
5:80076889:T:C	C643R	1.000
5:80076890:G:C	C643S	1.000
5:80076949:T:A	C663S	1.000
5:80076950:G:C	C663S	1.000
5:80077009:T:A	C683S	1.000
5:80077010:G:C	C683S	1.000
5:80078069:T:A	C703S	1.000
5:80078070:G:C	C703S	1.000
5:80078117:T:A	C719S	1.000
5:80078117:T:C	C719R	1.000
5:80078118:G:C	C719S	1.000
5:80078119:C:G	C719W	1.000
5:80078175:T:A	L738Q	1.000
5:80078175:T:C	L738P	1.000
5:80078178:A:G	D739G	1.000
5:80078186:G:A	G742R	1.000
5:80078186:G:C	G742R	1.000
5:80078186:G:T	G742W	1.000
5:80078197:G:C	Q745H	1.000
5:80078197:G:T	Q745H	1.000
5:80078205:C:A	P748H	1.000
5:80078205:C:G	P748R	1.000
5:80078210:T:A	W750R	1.000
5:80078210:T:C	W750R	1.000
5:80078211:G:C	W750S	1.000

dbSNP variants (sampled 300 via entrez): RS1000061489 (5:80003899 A>G), RS1000134493 (5:80013893 C>A,T), RS1000187041 (5:80013661 C>T), RS1000200550 (5:80059915 C>G), RS1000215503 (5:80034212 T>C), RS1000244940 (5:80046845 G>A,C), RS1000350510 (5:80053588 C>T), RS1000383299 (5:80053234 G>T), RS1000440097 (5:80063642 C>T), RS1000467562 (5:80012242 C>T), RS1000492923 (5:80031170 A>C), RS1000534990 (5:80076572 C>A,G,T), RS1000537992 (5:79996856 A>G), RS1000581458 (5:80083401 A>G), RS1000590518 (5:80010488 C>A,T)

Disease associations

OMIM: gene MIM:600715 | disease phenotypes: MIM:142623

GenCC curated gene-disease

Mondo (1): Hirschsprung disease, susceptibility to, 1 (MONDO:0007723)

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

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002707_9	Serum thyroid-stimulating hormone levels	6.000000e-06
GCST005580_90	Intraocular pressure	4.000000e-11
GCST005580_93	Intraocular pressure	5.000000e-11
GCST006585_1501	Blood protein levels	2.000000e-11
GCST010002_31	Refractive error	1.000000e-12
GCST90000654_20	Central corneal thickness	3.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
sodium arsenite	affects methylation, decreases expression	2
Doxorubicin	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression	2
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol S	increases expression	1
Decitabine	affects expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Etoposide	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Niclosamide	increases expression	1

Clinical trials (associated diseases)

48 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
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)
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
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
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
NCT06197061	Not specified	UNKNOWN	Comparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)
NCT06650683	Not specified	RECRUITING	Impact of Providing Nursing Support on Parental Stress Related to Preoperative Care of a Newborn with Hirschsprung’s Disease