ZIC3

Summary

ZIC3 (Zic family zinc finger 3, HGNC:12874) is a protein-coding gene on chromosome Xq26.3, encoding Zinc finger protein ZIC 3 (O60481). Acts as a transcriptional activator. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation. Mutations in this gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs.

Source: NCBI Gene 7547 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease with heterotaxy syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 201 total — 31 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 74
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12874
Approved symbol	ZIC3
Name	Zic family zinc finger 3
Location	Xq26.3
Locus type	gene with protein product
Status	Approved
Aliases	HTX, ZNF203
Ensembl gene	ENSG00000156925
Ensembl biotype	protein_coding
OMIM	300265
Entrez	7547

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000287538, ENST00000370606, ENST00000478471, ENST00000919832, ENST00000919833, ENST00000919834, ENST00000919835, ENST00000919836, ENST00000919837

RefSeq mRNA: 2 — MANE Select: NM_003413 NM_001330661, NM_003413

CCDS: CCDS14663, CCDS83494

Canonical transcript exons

ENST00000287538 — 3 exons

Exon	Start	End
ENSE00001029121	137569891	137572102
ENSE00001297697	137566127	137567751
ENSE00001610113	137568902	137569065

Expression profiles

Bgee: expression breadth broad, 81 present calls, max score 86.58.

FANTOM5 (CAGE): breadth broad, TPM avg 8.9840 / max 568.6879, expressed in 342 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197739	4.5580	310
197742	1.6684	248
197740	1.4511	209
197741	0.2390	117
197748	0.2319	109
197744	0.2253	120
197745	0.2062	105
197746	0.2037	93
197743	0.2004	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	86.58	gold quality
cerebellar hemisphere	UBERON:0002245	86.57	gold quality
cerebellar cortex	UBERON:0002129	86.51	gold quality
cerebellum	UBERON:0002037	85.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.21	gold quality
paraflocculus	UBERON:0005351	71.09	gold quality
ventricular zone	UBERON:0003053	70.58	gold quality
cerebellar vermis	UBERON:0004720	70.22	gold quality
embryo	UBERON:0000922	69.89	gold quality
ganglionic eminence	UBERON:0004023	67.48	gold quality
cranial nerve II	UBERON:0000941	63.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	63.34	gold quality
hypothalamus	UBERON:0001898	62.08	gold quality
spinal cord	UBERON:0002240	61.13	gold quality
right frontal lobe	UBERON:0002810	60.77	gold quality
putamen	UBERON:0001874	60.05	gold quality
prefrontal cortex	UBERON:0000451	59.64	gold quality
caudate nucleus	UBERON:0001873	58.89	gold quality
central nervous system	UBERON:0001017	58.86	gold quality
brain	UBERON:0000955	58.79	gold quality
epithelial cell of pancreas	CL:0000083	58.74	gold quality
calcaneal tendon	UBERON:0003701	58.66	gold quality
Brodmann (1909) area 9	UBERON:0013540	58.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.63	gold quality
substantia nigra	UBERON:0002038	57.23	gold quality
amygdala	UBERON:0001876	56.93	gold quality
nucleus accumbens	UBERON:0001882	56.81	gold quality
adenohypophysis	UBERON:0002196	56.53	gold quality
frontal cortex	UBERON:0001870	56.45	gold quality
neocortex	UBERON:0001950	56.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	10.34
E-ANND-3	yes	2.96

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
ACTA1	Unknown
HESX1	Unknown
NANOG	Activation
NPPA	Activation
TPM1

JASPAR motifs

Motif	Name	Family
MA0697.1	ZIC3	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:19443739

Upstream regulators (CollecTRI, top): AP1, MEIS1, NANOG, PBX1, POU5F1, SOX2

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• we have focused on the regulation of the Zic3 gene, which codes for a zinc finger transcription factor expressed in the organizer region at the beginning of gastrulation (PMID:12963115)
• ZIC3 mutations in three classic heterotaxy kindreds and two sporadic congenital heart defect cases (PMID:14681828)
• Results suggest that Zic3 plays a role in intra-retinal axon targeting, possibly through regulation of the expression of specific downstream genes involved in axon guidance. (PMID:14985256)
• A positional effect caused by the balanced (X;21) translocation may be responsible for functional nullisomy of ZIC3 (PMID:15470371)
• Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3. (PMID:17185387)
• We studied a series of 42 cases of transposition of the great arteries; mutation in the X chromosome at the ZIC3 gene was found in two affected siblings (one male, one female) and their unaffected mother (PMID:17295247)
• ZIC3 has a role in regulating cardiac gene expression (PMID:17468179)
• in vitro interactions of ZIC3 with GLI3 and the effect of ZIC3 mutations identified in patients with either heterotaxy or isolated cardiovascular malformations. (PMID:17764085)
• results indicate that ZIC3 is imported into the cell nucleus by the Karyopherin (Importin) system and that the impaired nuclear localization by the ZF1 mutation is not due to a direct influence on the nuclear localization signal (PMID:18716025)
• Disruption of Gli3-Zic3 interaction in the critical period for ventral body wall formation may contribute to omphalocele phenotype in Cd chick model. (PMID:21069353)
• Data show that transcript, termed Zic3-B, encompasses exons 1, 2, and 4 whereas Zic3-A encompasses exons 1, 2, and 3. (PMID:21858219)
• Mutations in Zinc Finger Protein of the Cerebellum 3 were identified in 4 of the 47 patients (8.5%) with heterotaxy syndrome. Our results expand the mutation spectrum of monogenic heterotaxy syndrome with associated cardiac anomalies. (PMID:21864452)
• Case Reports: situs inversus totalis and X-linked heterotaxy as a result of novel ZIC3 mutation. (PMID:22171628)
• ZIC3 mutations are an important etiology in sporadic and familial heterotaxy. (PMID:23427188)
• sumoylation targets human ZIC3 primarily on the consensus lysine residue K248, which is critical for the nuclear retention of ZIC3. (PMID:23872418)
• ZIC3 sequencing from unrelated patients with heterotaxy and congenital heart disease identified variants in 5.2% of sporadic male cases some of which were novel. Functional analyses show aberrant cytoplasmic localization. (PMID:24123890)
• Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association (PMID:26294094)
• detected the expression level of miR-564 and ZIC3 protein in tissue specimens, and found a significant negative correlation between them. Patients with low levels of miR-564 showed a poorer overall survival (PMID:26498524)
• Six novel pathogenic variants were identified in either male patients with heterotaxy or a female patient with multiple male deaths due to heterotaxy in the family. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins. (PMID:27406248)
• current understanding of ZIC3 function and describe the potential role ZIC3 plays in important signalling pathways and their links to heterotaxy. (PMID:29442328)
• The results of functional indicated that this ZIC3 mutation decreases transcriptional activity, affects the affinity of the GLI-binding site and results in aberrant cellular localization in transfected cells. (PMID:30120289)
• This study characterized cis-regulatory elements required for Zic3 expression. (PMID:30297839)
• miR-155-5p inhibits the viability of vascular smooth muscle cell via targeting FOS and ZIC3 to promote aneurysm formation (PMID:30898623)
• Description of a family with X-linked oculo-auriculo-vertebral spectrum associated with polyalanine tract expansion in ZIC3. (PMID:32639022)
• A novel ZIC3 mutation in a Chinese family with heterotaxy and multiple types of congenital heart defect. (PMID:36567274)
• Zic family member 3 attenuates oxidative stress-induced vascular smooth muscle cell apoptosis in patients with chronic kidney disease. (PMID:38091851)
• ZIC2 and ZIC3 promote SWI/SNF recruitment to safeguard progression towards human primed pluripotency. (PMID:39358345)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zic3	ENSDARG00000071497
mus_musculus	Zic3	ENSMUSG00000067860
rattus_norvegicus	Zic3	ENSRNOG00000000861

Paralogs (14): ZIC2 (ENSG00000043355), ZXDC (ENSG00000070476), GLI2 (ENSG00000074047), GLI3 (ENSG00000106571), GLIS3 (ENSG00000107249), GLI1 (ENSG00000111087), GLIS2 (ENSG00000126603), AEBP2 (ENSG00000139154), ZIC5 (ENSG00000139800), ZIC1 (ENSG00000152977), GLIS1 (ENSG00000174332), ZIC4 (ENSG00000174963), ZXDA (ENSG00000198205), ZXDB (ENSG00000198455)

Protein

Protein identifiers

Zinc finger protein ZIC 3 — O60481 (reviewed: O60481)

Alternative names: Zinc finger protein 203, Zinc finger protein of the cerebellum 3

All UniProt accessions (1): O60481

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5’-GGGTGGTC-3'.

Subunit / interactions. Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5); the interaction reduces its transcriptional activity. Interacts with KPNA1 and KPNA6. Interacts (via C2H2-type domains 3, 4 and 5) with GLI3; the interaction enhances its transcriptional activity.

Subcellular location. Nucleus. Cytoplasm.

Disease relevance. Heterotaxy, visceral, 1, X-linked (HTX1) [MIM:306955] A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can be associated with a variety of congenital defects including cardiac malformations. The disease is caused by variants affecting the gene represented in this entry. VACTERL association X-linked with or without hydrocephalus (VACTERLX) [MIM:314390] A syndrome characterized by a non-random association of congenital defects. Affected individuals manifest vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula (TE), renal anomalies (R) such as urethral atresia with hydronephrosis, and limb anomalies (L) such as hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb. Some patients may have hydrocephalus. Some cases of VACTERL-H are associated with increased chromosome breakage and rearrangement. The disease is caused by variants affecting the gene represented in this entry. Congenital heart defects, multiple types, 1, X-linked (CHTD1) [MIM:306955] A disorder characterized by congenital developmental abnormalities involving structures of the heart. Common defects include transposition of the great arteries, aortic stenosis, atrial septal defect, ventricular septal defect, pulmonic stenosis, and patent ductus arteriosus. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C2H2-type 3, 4 and 5 zinc finger domains are necessary for transcription activation.

Similarity. Belongs to the GLI C2H2-type zinc-finger protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60481-1	1, ZIC3-A	yes
O60481-2	2, ZIC3-B

RefSeq proteins (2): NP_001317590, NP_003404* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR041643	Znf_ZIC	Domain
IPR043359	GLI-like	Family
IPR056436	Znf-C2H2_ZIC1-5/GLI1-3-like	Domain

Pfam: PF00096, PF18366, PF23561

UniProt features (56 total): mutagenesis site 15, sequence variant 12, zinc finger region 5, strand 5, compositionally biased region 4, helix 4, turn 4, region of interest 2, short sequence motif 2, chain 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2EJ4	SOLUTION NMR
2RPC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60481-F1	54.97	0.00

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 (1): 248

Mutagenesis-validated functional residues (15):

Position	Phenotype
268	increases weakly its cytoplasmic localization.
281	increases its cytoplasmic localization.
304	increases its cytoplasmic localization.
307	increases its cytoplasmic localization.
310	increases its cytoplasmic localization.
312	increases its cytoplasmic localization.
314	does not increase its cytoplasmic localization.
320	increases its cytoplasmic localization. does not interact with kpna1 and kpna6 and increases strongly its cytoplasmic lo
326	does not increase its cytoplasmic localization.
337	increases its cytoplasmic localization. does not interact with kpna1 and kpna6 and increases strongly its cytoplasmic lo
341	increases its cytoplasmic localization. does not interact with kpna1 and kpna6 and increases strongly its cytoplasmic lo
346	increases its cytoplasmic localization. does not interact with kpna1 and kpna6 and increases strongly its cytoplasmic lo
349	increases its cytoplasmic localization. does not interacts with kpna1 and kpna6 and increases strongly its cytoplasmic l
350	increases its cytoplasmic localization. does not interact with kpna1 and kpna6 and increases strongly its cytoplasmic lo
356	does not increase its cytoplasmic localization.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2892247	POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation
R-HSA-452723	Transcriptional regulation of pluripotent stem cells

MSigDB gene sets: 460 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_PRIMITIVE_STREAK_FORMATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_NEUROGENESIS, ACTGCAG_MIR173P, AATGGAG_MIR136, GOBP_GASTRULATION_WITH_MOUTH_FORMING_SECOND, GGCNKCCATNK_UNKNOWN

GO Biological Process (43): skeletal system development (GO:0001501), neural plate development (GO:0001840), heart looping (GO:0001947), atrial cardiac muscle tissue development (GO:0003228), smoothened signaling pathway (GO:0007224), determination of left/right symmetry (GO:0007368), central nervous system development (GO:0007417), embryonic pattern specification (GO:0009880), hippocampus development (GO:0021766), olfactory bulb development (GO:0021772), neuron differentiation (GO:0030182), lung development (GO:0030324), germ-line stem cell population maintenance (GO:0030718), limb morphogenesis (GO:0035108), central nervous system segmentation (GO:0035283), determination of pancreatic left/right asymmetry (GO:0035469), determination of left/right asymmetry in nervous system (GO:0035545), outer ear morphogenesis (GO:0042473), mRNA transcription by RNA polymerase II (GO:0042789), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), axial mesoderm development (GO:0048318), paraxial mesoderm development (GO:0048339), stem cell differentiation (GO:0048863), face development (GO:0060324), left/right axis specification (GO:0070986), determination of digestive tract left/right asymmetry (GO:0071907), determination of liver left/right asymmetry (GO:0071910), primitive streak formation (GO:0090009), cranial skeletal system development (GO:1904888), regulation of transcription by RNA polymerase II (GO:0006357), gastrulation (GO:0007369), pattern specification process (GO:0007389), nervous system development (GO:0007399), mesoderm development (GO:0007498), heart development (GO:0007507), anterior/posterior pattern specification (GO:0009952), gene expression (GO:0010467), stem cell population maintenance (GO:0019827), cell differentiation (GO:0030154)

GO Molecular Function (12): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Transcriptional regulation of pluripotent stem cells	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
system development	2
nervous system development	2
anatomical structure development	2
determination of left/right symmetry	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
chordate embryonic development	1
epithelium development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
cardiac muscle tissue development	1
cell surface receptor signaling pathway	1
determination of bilateral symmetry	1
left/right pattern formation	1
pattern specification process	1
embryo development	1
pallium development	1
limbic system development	1
olfactory lobe development	1
cell differentiation	1
generation of neurons	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
stem cell population maintenance	1
appendage morphogenesis	1
limb development	1
central nervous system development	1
segmentation	1
pancreas development	1
ear morphogenesis	1
embryonic morphogenesis	1
transcription by RNA polymerase II	1
mRNA transcription	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1

Protein interactions and networks

STRING

1534 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZIC3	NODAL	Q96S42	923
ZIC3	LEFTY2	O00292	920
ZIC3	ACVR2B	Q13705	902
ZIC3	CFC1	P0CG37	897
ZIC3	GPR31	O00270	841
ZIC3	CRIPTO	P13385	808
ZIC3	LEFTY1	O75610	798
ZIC3	GJA1	P17302	754
ZIC3	SOX2	P48431	710
ZIC3	NANOG	Q9H9S0	697
ZIC3	POU5F1	P31359	693
ZIC3	PITX2	Q99697	677
ZIC3	GLI3	P10071	637
ZIC3	GLI1	P08151	627
ZIC3	FOXF1	Q12946	620

IntAct

36 interactions, top by confidence:

A	B	Type	Score
TP53	ZIC3	psi-mi:“MI:0915”(physical association)	0.400
CTNNB1	ZIC3	psi-mi:“MI:0915”(physical association)	0.400
TWIST1	ZIC3	psi-mi:“MI:0915”(physical association)	0.400
	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
CCL2	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
CCL22	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
CCL24	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
CCL3L1	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
CCL4L1	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
CSF2	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
CXCL5	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
IFNL4	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
IL18	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
IL23A	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
IL3	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
IL31	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
IL33	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
ZIC3	IL36B	psi-mi:“MI:0915”(physical association)	0.370
IL37	ZIC3	psi-mi:“MI:0915”(physical association)	0.370
XCL2	ZIC3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (30): GLI3 (Reconstituted Complex), SRF (Reconstituted Complex), ZIC3 (Reconstituted Complex), ZIC3 (Reconstituted Complex), ZIC3 (Reconstituted Complex), ZIC3 (Affinity Capture-MS), ZIC3 (Affinity Capture-MS), ZIC3 (Affinity Capture-MS), ZIC3 (Reconstituted Complex), MYO1C (Affinity Capture-MS), MYO1B (Affinity Capture-MS), MYO1D (Affinity Capture-MS), TPM3 (Affinity Capture-MS), TPM1 (Affinity Capture-MS), MYH10 (Affinity Capture-MS)

ESM2 similar proteins: A0JC51, A5ABV9, O08656, O09100, O18896, O57311, O60481, O73689, O95409, P09022, P10070, P19544, P22561, P23769, P23770, P23771, P23772, P23824, P25932, P46684, P49639, P49952, P54655, P55878, P70062, P70063, Q08DV0, Q0VGT2, Q15915, Q62520, Q62521, Q6DJQ6, Q6VVD7, Q6XP49, Q7TQ40, Q800Q5, Q8JJC0, Q91689, Q924A0, Q924Y4

Diamond homologs: A0A5K4F1D0, A0JC51, A4FV57, O57311, O60481, O73689, O95409, P08151, P10070, P10071, P19538, P34708, P39768, P46684, P47806, P55878, P55879, Q0VGT2, Q15915, Q17308, Q5IS56, Q61467, Q61602, Q62520, Q62521, Q6DJQ6, Q6GR30, Q6XP49, Q6ZN18, Q7JNM3, Q7K0S9, Q7SXV2, Q7TQ40, Q8JJC0, Q8K1M4, Q8N9L1, Q8NBF1, Q8NEA6, Q8SV95, Q8VDL9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ZIC3	up-regulates	GLI3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 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
Interleukin-10 signaling	5	64.7×	1e-06
Chemokine receptors bind chemokines	5	52.0×	2e-06
Interleukin-4 and Interleukin-13 signaling	6	34.3×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
chemokine-mediated signaling pathway	6	92.6×	4e-09
antimicrobial humoral immune response mediated by antimicrobial peptide	7	54.0×	4e-09
cytokine-mediated signaling pathway	5	31.1×	3e-05
cellular response to lipopolysaccharide	6	28.0×	4e-06
positive regulation of cell migration	9	26.5×	4e-09
inflammatory response	11	19.8×	5e-10
cell-cell signaling	5	16.6×	4e-04
immune response	7	15.7×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	10
Uncertain significance	95
Likely benign	28
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075476	NM_003413.4(ZIC3):c.860_864del (p.Val287fs)	Pathogenic
11433	NM_003413.4(ZIC3):c.968C>T (p.Thr323Met)	Pathogenic
11434	NM_003413.4(ZIC3):c.804C>A (p.Cys268Ter)	Pathogenic
11435	NM_003413.4(ZIC3):c.1222A>T (p.Lys408Ter)	Pathogenic
11436	NM_003413.4(ZIC3):c.745C>T (p.Gln249Ter)	Pathogenic
11437	NM_003413.4(ZIC3):c.758G>C (p.Cys253Ser)	Pathogenic
11438	NM_003413.4(ZIC3):c.1213A>G (p.Lys405Glu)	Pathogenic
11440	NM_003413.4(ZIC3):c.972_973insTT (p.Glu325fs)	Pathogenic
11441	NM_003413.4(ZIC3):c.763T>G (p.Trp255Gly)	Pathogenic
1416124	NM_003413.4(ZIC3):c.810del (p.Thr271fs)	Pathogenic
1707614	NM_003413.4(ZIC3):c.599del (p.Arg200fs)	Pathogenic
2118034	NM_003413.4(ZIC3):c.976A>T (p.Lys326Ter)	Pathogenic
2118751	NM_003413.4(ZIC3):c.727_740del (p.Met243fs)	Pathogenic
216089	NM_003413.3(ZIC3):c.(?-1)(*1_?)del	Pathogenic
2737377	NM_003413.4(ZIC3):c.463G>T (p.Glu155Ter)	Pathogenic
2814022	NM_003413.4(ZIC3):c.109_112del (p.Leu37fs)	Pathogenic
283617	NM_003413.4(ZIC3):c.1025del (p.Ser342fs)	Pathogenic
29955	NM_003413.4(ZIC3):c.163GCC[3] (p.Ala54_Ala55dup)	Pathogenic
3233415	NM_001330661.1(ZIC3):c.1224+3286A>G	Pathogenic
3725958	NM_003413.4(ZIC3):c.764G>A (p.Trp255Ter)	Pathogenic
4526004	NM_003413.4(ZIC3):c.312C>A (p.Tyr104Ter)	Pathogenic
464967	NM_003413.4(ZIC3):c.476_479del (p.Tyr159fs)	Pathogenic
4714750	NM_003413.4(ZIC3):c.208C>T (p.Gln70Ter)	Pathogenic
545552	NM_003413.4(ZIC3):c.755C>A (p.Ser252Ter)	Pathogenic
545553	NM_003413.4(ZIC3):c.757T>A (p.Cys253Ser)	Pathogenic
545554	NM_003413.4(ZIC3):c.128C>A (p.Ser43Ter)	Pathogenic
545555	NM_003413.4(ZIC3):c.593_609del (p.Pro198fs)	Pathogenic
570392	NM_003413.4(ZIC3):c.535dup (p.Val179fs)	Pathogenic
645837	NM_003413.4(ZIC3):c.571del (p.Glu191fs)	Pathogenic
853140	NM_003413.4(ZIC3):c.128C>G (p.Ser43Ter)	Pathogenic

SpliceAI

512 predictions. Top by Δscore:

Variant	Effect	Δscore
X:137567752:GTAAG:G	donor_loss	1.0000
X:137567753:T:A	donor_loss	1.0000
X:137568896:TTGCA:T	acceptor_loss	1.0000
X:137568897:TGCAG:T	acceptor_loss	1.0000
X:137568898:GCAGG:G	acceptor_loss	1.0000
X:137568899:CA:C	acceptor_loss	1.0000
X:137568900:AGGTG:A	acceptor_loss	1.0000
X:137568901:G:A	acceptor_loss	1.0000
X:137566286:G:GT	donor_gain	0.9800
X:137567752:G:GG	donor_gain	0.9800
X:137568900:A:AG	acceptor_gain	0.9800
X:137568901:G:GG	acceptor_gain	0.9800
X:137568901:GGT:G	acceptor_gain	0.9800
X:137568901:GGTGA:G	acceptor_gain	0.9800
X:137566191:C:T	donor_gain	0.9600
X:137567749:CAG:C	donor_gain	0.9600
X:137568900:AGGT:A	acceptor_gain	0.9600
X:137568901:GGTG:G	acceptor_gain	0.9600
X:137567747:CACAG:C	donor_gain	0.9300
X:137567748:ACAG:A	donor_gain	0.9200
X:137567750:AG:A	donor_gain	0.9200
X:137567751:GG:G	donor_gain	0.9200
X:137568890:T:TA	acceptor_gain	0.9200
X:137566280:ACCC:A	donor_gain	0.9100
X:137568808:G:T	donor_gain	0.9100
X:137568900:AG:A	acceptor_gain	0.9000
X:137568901:GG:G	acceptor_gain	0.9000
X:137570981:A:AG	acceptor_gain	0.8900
X:137570982:G:GG	acceptor_gain	0.8900
X:137570982:GT:G	acceptor_gain	0.8900

AlphaMissense

3100 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:137567448:T:C	C253R	1.000
X:137567505:T:C	F272L	1.000
X:137567506:T:C	F272S	1.000
X:137567507:C:A	F272L	1.000
X:137567507:C:G	F272L	1.000
X:137567524:T:C	L278P	1.000
X:137567595:T:C	C302R	1.000
X:137567616:T:C	F309L	1.000
X:137567618:C:A	F309L	1.000
X:137567618:C:G	F309L	1.000
X:137567635:T:C	L315P	1.000
X:137567643:C:A	H318N	1.000
X:137567643:C:G	H318D	1.000
X:137567644:A:C	H318P	1.000
X:137567645:C:A	H318Q	1.000
X:137567645:C:G	H318Q	1.000
X:137567650:G:C	R320P	1.000
X:137567679:T:A	C330S	1.000
X:137567679:T:C	C330R	1.000
X:137567680:G:A	C330Y	1.000
X:137567680:G:C	C330S	1.000
X:137567681:C:G	C330W	1.000
X:137567694:T:C	C335R	1.000
X:137567696:C:G	C335W	1.000
X:137567706:T:C	F339L	1.000
X:137567707:T:C	F339S	1.000
X:137567708:T:A	F339L	1.000
X:137567708:T:G	F339L	1.000
X:137567712:C:A	R341S	1.000
X:137567725:T:C	L345P	1.000

dbSNP variants (sampled 300 via entrez): RS1000638217 (X:137568350 CT>C), RS1000785206 (X:137569873 T>C), RS1000903067 (X:137569264 AG>A), RS1000933934 (X:137569369 C>G,T), RS1001060613 (X:137577994 A>C), RS1001368262 (X:137569002 C>T), RS1001411581 (X:137568785 C>T), RS1001623198 (X:137571363 A>G), RS1001758845 (X:137570915 CTT>C), RS1001955002 (X:137568029 G>T), RS1002870728 (X:137564525 T>C), RS1002935112 (X:137573774 G>A), RS1003202936 (X:137566126 T>G), RS1003297640 (X:137574790 G>A), RS1003376737 (X:137573493 G>A)

Disease associations

OMIM: gene MIM:300265 | disease phenotypes: MIM:306955, MIM:314390, MIM:300942

GenCC curated gene-disease

Disease	Classification	Inheritance
heterotaxy, visceral, 1, X-linked	Definitive	X-linked
VACTERL association, X-linked, with or without hydrocephalus	Definitive	X-linked
congenital heart disease with heterotaxy syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease with heterotaxy syndrome	Definitive	XL

Mondo (5): heterotaxy, visceral, 1, X-linked (MONDO:0010607), VACTERL association, X-linked, with or without hydrocephalus (MONDO:0010752), congenital heart defects, multiple types, 1, X-linked (MONDO:0800321), X-linked acrogigantism due to Xq26 microduplication (MONDO:0010491), congenital heart disease with heterotaxy syndrome (MONDO:1060197)

Orphanet (4): Visceral heterotaxy (Orphanet:450), VACTERL with hydrocephalus (Orphanet:3412), X-linked acrogigantism (Orphanet:300373), OBSOLETE: X-linked acrogigantism due to Xq26 microduplication (Orphanet:448372)

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000068	Urethral atresia
HP:0000085	Horseshoe kidney
HP:0000104	Renal agenesis
HP:0000105	Enlarged kidney
HP:0000126	Hydronephrosis
HP:0000238	Hydrocephalus
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000925	Abnormality of the vertebral column
HP:0000960	Sacral dimple
HP:0000961	Cyanosis
HP:0001161	Hand polydactyly
HP:0001321	Cerebellar hypoplasia
HP:0001374	Congenital hip dislocation
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001539	Omphalocele
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001640	Cardiomegaly
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001651	Dextrocardia
HP:0001655	Patent foramen ovale
HP:0001669	Transposition of the great arteries
HP:0001674	Complete atrioventricular canal defect
HP:0001680	Coarctation of aorta
HP:0001682	Subvalvular aortic stenosis
HP:0001718	Mitral stenosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_96	Refractive error	2.000000e-15

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538116	Heterotaxy, visceral, X-linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, increases methylation, affects cotreatment	7
trichostatin A	affects cotreatment, increases expression, affects expression, decreases reaction	4
entinostat	affects cotreatment, increases expression	2
belinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
TAK-243	increases sumoylation	1
methylmercuric chloride	increases expression	1
decabromobiphenyl ether	increases expression	1
terbufos	increases methylation	1
tetrabromobisphenol A	increases expression	1
butylbenzyl phthalate	decreases expression	1
tetrachlorodian	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Vorinostat	increases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Fonofos	increases methylation	1
Estradiol	decreases expression	1
Nickel	affects expression, decreases reaction	1
Parathion	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silver	decreases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A8C6	SEES3-1V human ZIC3, clone1	Embryonic stem cell	Male
CVCL_A8C7	SEES3-1V human ZIC3, clone2	Embryonic stem cell	Male
CVCL_A8C8	SEES3-1V human ZIC3, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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