ZHX2

Summary

ZHX2 (zinc fingers and homeoboxes 2, HGNC:18513) is a protein-coding gene on chromosome 8q24.13, encoding Zinc fingers and homeoboxes protein 2 (Q9Y6X8). Acts as a transcriptional repressor.

The members of the zinc fingers and homeoboxes gene family are nuclear homodimeric transcriptional repressors that interact with the A subunit of nuclear factor-Y (NF-YA) and contain two C2H2-type zinc fingers and five homeobox DNA-binding domains. This gene encodes member 2 of this gene family. In addition to forming homodimers, this protein heterodimerizes with member 1 of the zinc fingers and homeoboxes family.

Source: NCBI Gene 22882 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 146 total
• Transcription factor: yes — 104 downstream targets (CollecTRI)
• MANE Select transcript: NM_014943

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18513
Approved symbol	ZHX2
Name	zinc fingers and homeoboxes 2
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0854
Ensembl gene	ENSG00000178764
Ensembl biotype	protein_coding
OMIM	609185
Entrez	22882

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000314393, ENST00000534247, ENST00000892386, ENST00000892387, ENST00000892388, ENST00000892389, ENST00000892390, ENST00000892391, ENST00000892392, ENST00000892393, ENST00000892394, ENST00000923896, ENST00000923897, ENST00000970101, ENST00000970102

RefSeq mRNA: 20 — MANE Select: NM_014943 NM_001362797, NM_001412796, NM_001412797, NM_001412798, NM_001412799, NM_001412800, NM_001412801, NM_001412802, NM_001412803, NM_001412804, NM_001412805, NM_001412806, NM_001412807, NM_001412808, NM_001412809, NM_001412810, NM_001412811, NM_001412812, NM_001412813, NM_014943

CCDS: CCDS6336

Canonical transcript exons

ENST00000314393 — 4 exons

Exon	Start	End
ENSE00001252625	122951292	122954028
ENSE00001292641	122863477	122863539
ENSE00001310974	122781655	122781946
ENSE00001326276	122973242	122974510

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 93.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8449 / max 238.9771, expressed in 1662 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90452	3.7645	719
90450	2.9865	1103
90455	2.4293	1120
90451	1.8855	817
90454	0.4346	111
90461	0.4110	171
90449	0.2591	119
90447	0.1654	82
90448	0.1543	62
205306	0.1476	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
superficial temporal artery	UBERON:0001614	93.45	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.35	gold quality
saphenous vein	UBERON:0007318	93.33	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.14	gold quality
inferior olivary complex	UBERON:0002127	92.95	gold quality
medial globus pallidus	UBERON:0002477	92.64	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.31	gold quality
biceps brachii	UBERON:0001507	92.28	gold quality
globus pallidus	UBERON:0001875	92.24	gold quality
heart right ventricle	UBERON:0002080	91.76	gold quality
caput epididymis	UBERON:0004358	91.64	gold quality
mammary duct	UBERON:0001765	91.61	gold quality
germinal epithelium of ovary	UBERON:0001304	91.59	gold quality
left ventricle myocardium	UBERON:0006566	91.16	gold quality
cartilage tissue	UBERON:0002418	90.92	gold quality
cauda epididymis	UBERON:0004360	90.74	gold quality
urethra	UBERON:0000057	90.71	gold quality
cranial nerve II	UBERON:0000941	90.55	gold quality
skeletal muscle tissue	UBERON:0001134	90.47	gold quality
epithelium of mammary gland	UBERON:0003244	90.41	gold quality
gastrocnemius	UBERON:0001388	90.40	gold quality
vastus lateralis	UBERON:0001379	90.16	gold quality
synovial joint	UBERON:0002217	90.15	gold quality
muscle organ	UBERON:0001630	90.00	gold quality
skeletal muscle organ	UBERON:0014892	90.00	gold quality
quadriceps femoris	UBERON:0001377	89.98	gold quality
muscle of leg	UBERON:0001383	89.86	gold quality
inferior vagus X ganglion	UBERON:0005363	89.51	gold quality
lower lobe of lung	UBERON:0008949	89.43	gold quality
lymph node	UBERON:0000029	89.34	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	21.39
E-ANND-3	yes	6.22
E-GEOD-110499	no	559.62

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

104 targets.

Target	Regulation
ABCB1
ABL1
ACTB
ADAM2
ADRB1
AFP	Repression
AGT
ALOX12
ARAF
CALCA
CCL2
CCNA2	Repression
CCND1
CCNE1	Repression
CDC25C	Repression
CDH1
CDKN1A
CDKN1B
CDKN2A
CLASP1
CRH
CSTA
CXCL8
DCN
DMP1
EGF
EGFR
EGR1
EPHB2
FGF1

Upstream regulators (CollecTRI, top): MSX1, XBP1, ZHX2, ZHX3

miRNA regulators (miRDB)

134 targeting ZHX2, 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-4668-3P	100.00	68.74	2635
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-106A-5P	99.90	73.94	2683

Literature-anchored findings (GeneRIF, showing 34)

• identification as a transcriptional repressor (PMID:12741956)
• ZHX2, a transcriptional repressor, may participate in globin gene regulation. (PMID:16952470)
• ZHX proteins 1, 2 and 3 are major transcriptional mediators of podocyte disease (PMID:17056598)
• High ZHX2 is associated with metastasis in hepatocellular carcinoma. (PMID:17447851)
• These data support the idea that ZHX2 contributes to AFP repression in the liver after birth and may also be involved in AFP reactivation in liver cancer. (PMID:18194454)
• There was no significant difference in high and low percentage of HbF in GG, GA, and AA bearing individuals showing that ZHX2 gene variant has no role in ameliorating the severity of beta-thalassemia major in the South Indian population from Andhra Pradesh. (PMID:21443521)
• Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. (PMID:21987443)
• results demonstrate multiple mechanisms decreasing expression of tumor suppressor gene ZHX2 in Hodgkin lymphoma cell lines (PMID:22078940)
• simultaneous application of ZFN and rescue DNA induced gene repair of the disease-causing mutation on the genomic level, resulting in recovery of protein expression. (PMID:22661463)
• Expression of a constitutively active Raf transgene enhances lymphoproliferation, indicating a role for the Ras-MAPK pathway in linker for activation of T cells (LAT)-mediated autoimmune hyperproliferation. (PMID:22984075)
• Data indicate that zinc-fingers and homeoboxes 2 (ZHX2) suppresses glypican 3 (GPC3) transcription by binding with its core promoter. (PMID:25195714)
• Data show that Zinc-fingers and homeoboxes 2 (ZHX2) represses nuclear transcription factor Y alpha (NF-Y)-mediated activation of multidrug resistance 1 (MDR1) transcription. (PMID:25473899)
• Two novel markers, rs7840785 (PINX1) and rs7844465 (ZHX2), are significantly associated with carotid intima-media thickness. (PMID:25746325)
• These results indicated that ZHX2 plays a critical role in the proliferation and osteo/odontogenic differentiation of SCAPs. (PMID:26679602)
• ZHX2 expression in renal cell carcinoma (PMID:28152006)
• Zhx2 is a novel regulator of Mup expression; Zhx2 activates as well as represses expression of target genes (PMID:28258223)
• Remarkably, ZHX2 significantly decreased hepatitis B virus antigen expression, pregenomic RNA (pgRNA) and hepatitis B virus core particle DNA production both in vitro and in mouse livers supporting. (PMID:29580980)
• data indicate that HCC-promoting properties of HBV may include ZHX2 silencing via a miR-155 dependent pathway and suggests a novel therapy for HBV-related HCC (PMID:29752719)
• These studies reveal ZHX2 as a potential therapeutic target for clear cell renal cell carcinoma. (PMID:30026228)
• the expression profiles of ZHX2 and PTEN were positively correlated in hepatocellular carcinoma tissues (PMID:30784286)
• ZHX2 could inhibit proliferation and promote apoptosis of lung cancer cells by inhibiting p38MAPK signaling pathway. (PMID:31683461)
• Tumor suppressor ZHX2 inhibits NAFLD-HCC progression via blocking LPL-mediated lipid uptake. (PMID:31740790)
• The zinc fingers and homeoboxes 2 protein ZHX2 and its interacting proteins regulate upstream pathways in podocyte diseases. (PMID:32059999)
• ZHX2 restricts hepatocellular carcinoma by suppressing stem cell-like traits through KDM2A-mediated H3K36 demethylation. (PMID:32114388)
• ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma. (PMID:32382017)
• ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p. (PMID:32770671)
• HNRNPD interacts with ZHX2 regulating the vasculogenic mimicry formation of glioma cells via linc00707/miR-651-3p/SP2 axis. (PMID:33542193)
• Upregulation of ZHX2 predicts poor prognosis and is correlated with immune infiltration in gastric cancer. (PMID:33837660)
• Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity. (PMID:34279541)
• USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer. (PMID:36037364)
• Zinc fingers and homeoboxes 2 inhibition could suppress the proliferation of ovarian cancer cells by apoptosis pathway. (PMID:36746874)
• Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response. (PMID:37582865)
• Elongation of very long chain fatty acids-3 (Elovl3) is activated by ZHX2 and is a regulator of cell cycle progression. (PMID:37847682)
• METTL3 and IGF2BP1-Mediated m6A Modification of ZHX2 Promotes Tumor Property of Renal Cell Carcinoma. (PMID:39159608)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	zhx2a	ENSDARG00000055162
danio_rerio	zhx2b	ENSDARG00000101559
mus_musculus	Zhx2	ENSMUSG00000071757
rattus_norvegicus	Zhx2	ENSRNOG00000005417

Paralogs (3): ZHX1 (ENSG00000165156), ZHX3 (ENSG00000174306), HOMEZ (ENSG00000290292)

Protein

Protein identifiers

Zinc fingers and homeoboxes protein 2 — Q9Y6X8 (reviewed: Q9Y6X8)

Alternative names: Alpha-fetoprotein regulator 1, Regulator of AFP, Zinc finger and homeodomain protein 2

All UniProt accessions (2): H0YKA3, Q9Y6X8

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional repressor. Represses the promoter activity of the CDC25C gene stimulated by NFYA. May play a role in retinal development where it regulates the composition of bipolar cell populations, by promoting differentiation of bipolar OFF-type cells. In the brain, may promote maintenance and suppress differentiation of neural progenitor cells in the developing cortex.

Subunit / interactions. Homodimer (via homeobox domain). Heterodimer with ZHX1 (via homeobox domain 1). Heterodimer with ZHX3 (via homeobox domain 1). Heterodimerization with ZHX1 is not necessary for repressor activity. Interacts (via homeobox domain) with NFYA (via N-terminus). Interacts with EFNB1 intracellular domain peptide; the interaction enhances ZHX2 transcriptional repression activity.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed. Expressed in podocytes.

Similarity. Belongs to the ZHX family.

RefSeq proteins (20): NP_001349726, NP_001399725, NP_001399726, NP_001399727, NP_001399728, NP_001399729, NP_001399730, NP_001399731, NP_001399732, NP_001399733, NP_001399734, NP_001399735, NP_001399736, NP_001399737, NP_001399738, NP_001399739, NP_001399740, NP_001399741, NP_001399742, NP_055758* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR041057	ZHX_Znf_C2H2	Domain

Pfam: PF00046, PF18387

UniProt features (34 total): region of interest 8, helix 7, modified residue 4, DNA-binding region 4, compositionally biased region 3, sequence variant 3, zinc finger region 2, cross-link 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3NAU	X-RAY DIFFRACTION	2.7
2DMP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6X8-F1	60.42	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 (6): 37, 207, 825, 827, 64, 455

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 342 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_97, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, ZHAN_MULTIPLE_MYELOMA_PR_DN, HNF3ALPHA_Q6, PAX4_01, GAANYNYGACNY_UNKNOWN, TGCACTT_MIR519C_MIR519B_MIR519A, GOZGIT_ESR1_TARGETS_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_182, GOBP_NEUROGENESIS, MEF2_02

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), mRNA catabolic process (GO:0006402), central nervous system neuron differentiation (GO:0021953), somatic stem cell population maintenance (GO:0035019), negative regulation of neuron differentiation (GO:0045665), negative regulation of DNA-templated transcription (GO:0045892), retinal bipolar neuron differentiation (GO:0060040), nervous system development (GO:0007399), cell differentiation (GO:0030154)

GO Molecular Function (8): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
neuron differentiation	2
protein dimerization activity	2
negative regulation of DNA-templated transcription	1
RNA catabolic process	1
negative regulation of gene expression	1
mRNA metabolic process	1
central nervous system development	1
stem cell population maintenance	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
neural retina development	1
retina morphogenesis in camera-type eye	1
glutamatergic neuron differentiation	1
system development	1
cellular developmental process	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
transition metal ion binding	1
protein binding	1
identical protein binding	1
binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

1327 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZHX2	ZBTB20	Q9HC78	847
ZHX2	AFP	P02771	774
ZHX2	SLC25A37	Q9NYZ2	763
ZHX2	EFNB1	P98172	705
ZHX2	GGT1	P19440	652
ZHX2	SAP30	O75446	628
ZHX2	SAP18	O00422	620
ZHX2	A0A0J9YYA3	A0A0J9YYA3	588
ZHX2	HBA1	P01922	565
ZHX2	AFM	P43652	518
ZHX2	EFNB3	Q15768	490
ZHX2	CDC25C	P30307	489
ZHX2	ZHX3	Q9H4I2	485
ZHX2	TMEM170A	Q8WVE7	482
ZHX2	EFNB2	P52799	474

IntAct

87 interactions, top by confidence:

A	B	Type	Score
VHL	ELOC	psi-mi:“MI:0914”(association)	0.920
ZHX2	VHL	psi-mi:“MI:0915”(physical association)	0.610
VHL	ZHX2	psi-mi:“MI:0915”(physical association)	0.610
ZHX2	VHL	psi-mi:“MI:0914”(association)	0.610
ZHX1	ZHX2	psi-mi:“MI:0915”(physical association)	0.590
RELA	ZHX2	psi-mi:“MI:0915”(physical association)	0.580
ZHX2	RELA	psi-mi:“MI:0915”(physical association)	0.580
ZHX2	TFF2	psi-mi:“MI:0915”(physical association)	0.560
ABITRAM	POTEF	psi-mi:“MI:0914”(association)	0.530
MTHFD2L	MTHFD2	psi-mi:“MI:0914”(association)	0.530
ZHX2	ZHX2	psi-mi:“MI:0915”(physical association)	0.510
	ZHX2	psi-mi:“MI:0407”(direct interaction)	0.440
Arfgap1	ZHX2	psi-mi:“MI:0883”(gtpase reaction)	0.440
PARP2	ZHX2	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
ZHX2	AIFM1	psi-mi:“MI:0915”(physical association)	0.400
NFYA	ZHX2	psi-mi:“MI:0915”(physical association)	0.400
DHRS2	ZHX2	psi-mi:“MI:0915”(physical association)	0.370
LAT	ZHX2	psi-mi:“MI:0915”(physical association)	0.370
NAGPA	ZHX2	psi-mi:“MI:0915”(physical association)	0.370
Zhx2	ZHX2	psi-mi:“MI:0915”(physical association)	0.370
ZHX2	Nfya	psi-mi:“MI:0915”(physical association)	0.370
E6	TRAFD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): ZHX2 (Affinity Capture-MS), ZHX2 (Affinity Capture-MS), ZHX2 (Affinity Capture-MS), ZHX2 (Affinity Capture-RNA), VHL (Affinity Capture-Western), RELA (Affinity Capture-Western), NFKB2 (Affinity Capture-Western), RELB (Affinity Capture-Western), NFKB1 (Affinity Capture-Western), ZHX2 (Affinity Capture-MS), ZHX3 (Reconstituted Complex), ZHX2 (Reconstituted Complex), ZHX2 (Two-hybrid), ZHX2 (Proximity Label-MS), ZHX2 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0R4IYX6, A0A1L8H0H2, A5X7A0, A7XYJ6, E1BE02, F6NSX9, F8VPJ6, O35914, O57415, P37275, P59598, P59759, Q03172, Q13029, Q2KHR2, Q3UH06, Q5EXX3, Q5R7F2, Q5ZIE8, Q5ZLR2, Q62947, Q63755, Q64318, Q6NRM0, Q6ZPY7, Q76L83, Q7LBC6, Q7YR76, Q80VX4, Q86V15, Q8BHZ4, Q8BLG0, Q8BRH4, Q8BX22, Q8BZ32, Q8C0C0, Q8IZQ8, Q8NEZ4, Q8R5I7, Q8VIM5

Diamond homologs: A1YF22, A1YG99, A2T771, A2T7S4, P70121, Q5R7F2, Q80VX4, Q80Z36, Q8C0C0, Q8C0Q2, Q8IX15, Q8R515, Q9H4I2, Q9UKY1, Q9Y6X8, Q80W88, Q8K3E9, Q61321, Q9UIU6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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.

GO biological processes:

GO term	Partners	Fold	FDR
transcription by RNA polymerase II	9	9.8×	4e-05
neuron differentiation	6	9.3×	2e-03
negative regulation of cell migration	5	8.6×	8e-03
brain development	6	7.3×	6e-03
chromatin remodeling	6	6.7×	8e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	128
Likely benign	7
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2672 predictions. Top by Δscore:

Variant	Effect	Δscore
8:122900844:GCCAT:G	donor_gain	1.0000
8:122781617:G:GA	donor_gain	0.9900
8:122783010:G:GT	donor_gain	0.9900
8:122863471:CTGTA:C	acceptor_loss	0.9900
8:122863472:TGTA:T	acceptor_loss	0.9900
8:122863473:GTAG:G	acceptor_loss	0.9900
8:122863474:TAGGT:T	acceptor_loss	0.9900
8:122863475:A:AG	acceptor_gain	0.9900
8:122863475:AGGT:A	acceptor_loss	0.9900
8:122863476:G:GG	acceptor_gain	0.9900
8:122863535:GACCG:G	donor_gain	0.9900
8:122863539:GGT:G	donor_loss	0.9900
8:122863540:G:GG	donor_gain	0.9900
8:122863540:GTG:G	donor_loss	0.9900
8:122863541:T:TC	donor_loss	0.9900
8:122863542:GAGTA:G	donor_loss	0.9900
8:122863543:A:AC	donor_loss	0.9900
8:122900849:G:GG	donor_gain	0.9900
8:122955128:AAT:A	acceptor_gain	0.9900
8:122955128:AATG:A	acceptor_gain	0.9900
8:122972618:T:G	acceptor_gain	0.9900
8:122973236:TTCTA:T	acceptor_loss	0.9900
8:122973237:TCTA:T	acceptor_loss	0.9900
8:122973238:CTA:C	acceptor_loss	0.9900
8:122973240:A:G	acceptor_loss	0.9900
8:122973241:GGGA:G	acceptor_gain	0.9900
8:122973241:GGGAA:G	acceptor_gain	0.9900
8:122781452:T:G	donor_gain	0.9800
8:122781614:G:GA	donor_gain	0.9800
8:122863544:G:C	donor_loss	0.9800

AlphaMissense

5496 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:122951748:T:A	C80S	1.000
8:122951748:T:C	C80R	1.000
8:122951749:G:A	C80Y	1.000
8:122951749:G:C	C80S	1.000
8:122951750:C:G	C80W	1.000
8:122951757:T:C	C83R	1.000
8:122951759:C:G	C83W	1.000
8:122951787:T:C	F93L	1.000
8:122951788:T:C	F93S	1.000
8:122951788:T:G	F93C	1.000
8:122951789:C:A	F93L	1.000
8:122951789:C:G	F93L	1.000
8:122951800:T:A	V97D	1.000
8:122951811:C:G	H101D	1.000
8:122951813:T:A	H101Q	1.000
8:122951813:T:G	H101Q	1.000
8:122951844:T:C	C112R	1.000
8:122951845:G:A	C112Y	1.000
8:122951846:T:G	C112W	1.000
8:122951853:T:A	C115S	1.000
8:122951853:T:C	C115R	1.000
8:122951854:G:C	C115S	1.000
8:122951884:T:C	L125P	1.000
8:122951907:C:G	H133D	1.000
8:122952352:T:C	F281S	1.000
8:122952360:T:C	F284L	1.000
8:122952361:T:C	F284S	1.000
8:122952362:T:A	F284L	1.000
8:122952362:T:G	F284L	1.000
8:122952366:T:C	Y286H	1.000

dbSNP variants (sampled 300 via entrez): RS1000004112 (8:122939530 A>G), RS1000027319 (8:122846295 G>A,C,T), RS1000035143 (8:122939291 G>A), RS1000058693 (8:122970400 TG>T,TGG), RS1000077296 (8:122974461 G>T), RS1000086017 (8:122852462 G>A), RS1000092343 (8:122891881 G>C), RS1000092677 (8:122828069 T>C), RS1000101044 (8:122871583 C>A,T), RS1000116900 (8:122895070 T>C), RS1000117955 (8:122794740 C>T), RS1000140481 (8:122791124 A>G), RS1000151963 (8:122851041 C>T), RS1000157520 (8:122869883 CT>C), RS1000176972 (8:122874677 T>G)

Disease associations

OMIM: gene MIM:609185 | 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

10 associations (top):

Study	Trait	p-value
GCST001231_5	Carotid intima media thickness	2.000000e-11
GCST001491_26	Immune response to smallpox vaccine (IL-6)	1.000000e-08
GCST003989_38	Chin dimples	5.000000e-10
GCST007436_9	Carotid intima media thickness	3.000000e-11
GCST90000025_374	Appendicular lean mass	1.000000e-13
GCST90002396_436	Mean reticulocyte volume	6.000000e-18
GCST90002396_437	Mean reticulocyte volume	1.000000e-18
GCST90002397_348	Mean spheric corpuscular volume	7.000000e-15
GCST90002397_349	Mean spheric corpuscular volume	7.000000e-15
GCST90002405_521	Reticulocyte count	2.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004980	appendicular lean mass
EFO:0010701	mean reticulocyte volume
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17289471	ZHX2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	8
Benzo(a)pyrene	affects methylation, decreases expression	6
methylmercuric chloride	affects cotreatment, increases expression	4
bisphenol A	decreases expression, decreases methylation, increases expression, increases methylation	3
trichostatin A	affects cotreatment, increases expression	3
(+)-JQ1 compound	decreases expression	3
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Formaldehyde	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
geraniol	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases 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, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression, affects cotreatment	1
NSC 689534	affects binding, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Cannabidiol	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