ZIC1

Summary

ZIC1 (Zic family zinc finger 1, HGNC:12872) is a protein-coding gene on chromosome 3q24, encoding Zinc finger protein ZIC 1 (Q15915). Acts as a transcriptional activator.

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development. Aberrant expression of this gene is seen in medulloblastoma, a childhood brain tumor. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 4, a related family member on chromosome 3. This gene encodes a transcription factor that can bind and transactivate the apolipoprotein E gene.

Source: NCBI Gene 7545 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniosynostosis 6 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 205 total — 6 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 43
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_003412

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12872
Approved symbol	ZIC1
Name	Zic family zinc finger 1
Location	3q24
Locus type	gene with protein product
Status	Approved
Aliases	ZIC, ZNF201
Ensembl gene	ENSG00000152977
Ensembl biotype	protein_coding
OMIM	600470
Entrez	7545

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000282928, ENST00000472523, ENST00000474034, ENST00000481840, ENST00000488404

RefSeq mRNA: 1 — MANE Select: NM_003412 NM_003412

CCDS: CCDS3136

Canonical transcript exons

ENST00000282928 — 3 exons

Exon	Start	End
ENSE00001153530	147409365	147411094
ENSE00001206899	147413354	147416719
ENSE00001694509	147412518	147412681

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 99.82.

FANTOM5 (CAGE): breadth broad, TPM avg 10.9407 / max 990.5121, expressed in 697 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39030	5.9531	478
39018	2.1741	534
39037	0.6190	177
39057	0.5448	193
39023	0.5411	285
39035	0.2603	74
39056	0.2589	88
202959	0.2227	131
39038	0.0825	44
39058	0.0767	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
paraflocculus	UBERON:0005351	99.82	gold quality
cranial nerve II	UBERON:0000941	99.38	gold quality
cerebellum	UBERON:0002037	99.38	gold quality
cerebellar hemisphere	UBERON:0002245	99.36	gold quality
cerebellar cortex	UBERON:0002129	99.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.06	gold quality
pons	UBERON:0000988	99.04	gold quality
choroid plexus epithelium	UBERON:0003911	98.99	gold quality
adult organism	UBERON:0007023	98.57	gold quality
endothelial cell	CL:0000115	97.84	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.55	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.37	gold quality
trigeminal ganglion	UBERON:0001675	95.61	gold quality
cerebellar vermis	UBERON:0004720	95.46	gold quality
inferior olivary complex	UBERON:0002127	94.27	gold quality
olfactory bulb	UBERON:0002264	93.67	gold quality
medial globus pallidus	UBERON:0002477	92.59	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.34	gold quality
inferior vagus X ganglion	UBERON:0005363	92.20	gold quality
globus pallidus	UBERON:0001875	91.97	gold quality
corpus callosum	UBERON:0002336	91.72	gold quality
hypothalamus	UBERON:0001898	91.44	gold quality
medulla oblongata	UBERON:0001896	90.69	gold quality
dorsal root ganglion	UBERON:0000044	89.76	gold quality
spinal cord	UBERON:0002240	89.68	gold quality
nucleus accumbens	UBERON:0001882	89.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.23	gold quality
putamen	UBERON:0001874	88.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.41	gold quality
lateral globus pallidus	UBERON:0002476	87.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	693.56
E-HCAD-35	yes	9.90
E-ANND-3	yes	4.02

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets.

Target	Regulation
ABHD14A	Unknown
APOE	Unknown
ATOH1	Repression
BCL2L13	Activation
CCND1	Activation
CDKN1A	Activation
CDKN1B	Activation
CTNNB1
CYP26A1	Unknown
DR1	Repression
EIF3M	Activation
JUND	Activation
MYF5	Unknown
TLCD3A	Activation
WNT1	Activation
WNT4	Activation
WNT8B	Activation

JASPAR motifs

Motif	Name	Family
MA0696.1	ZIC1	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:19443739

Upstream regulators (CollecTRI, top): LMX1B

miRNA regulators (miRDB)

164 targeting ZIC1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-126-5P	100.00	72.71	3180
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3065-5P	99.97	71.56	3281

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 34)

• zic-1-mediated transcription is repressed by the intracellular domain of teneurin-2 (PMID:12783990)
• ZIC1 was excluded from playing a causal role in most cases of JS (Joubert syndrome) as no disease-associated mutations were identified. (PMID:14981711)
• Through physical mapping of 3q2 interstitial deletions in several individuals with Dandy-Walker malformation (DWM), we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. (PMID:15338008)
• this is the first report describing ZIC1 expression in mesenchymal proliferations and a role for DNA methylation in the control of ZIC1 expression. (PMID:17936758)
• Study investigated the effect of an evolutionarily conserved GQ from the mRNA of the zinc-finger protein of the cerebellum 1 (Zic-1); the motif was found to drastically repress translation without affecting the mRNA level in vivo. (PMID:18515550)
• These results revealed ZIC1 as a novel candidate tumor suppressor gene downregulated through promoter hypermethylation in gastric cancer. (PMID:19135984)
• ZIC1, ZIC2, and ZIC5 may have roles in meningiomas (PMID:20199689)
• ZIC1 contributes to the pathogenesis of liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round cell liposarcoma cell lines. (PMID:20713527)
• Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion. (PMID:21204220)
• ZIC1 may potentially function as a tumor suppressor gene (PMID:21347233)
• The down-regulated expression of ZIC1 and KLOTHO in colorectal carcinoma may relate to promoter methylation. (PMID:21671493)
• Overexpression of ZIC1 results in inactivation of Shh, PI(3)K and MAPK signaling pathways, as well as regulation of multiple downstream targets which are essential for the development and progression of gastric cancer. (PMID:22799764)
• Methylation of ZIC1, a putative tumor suppressor, may be a novel determinant of ovarian cancer outcome (PMID:23774800)
• Zic transcription factors function in patterning hindbrain motor neurons through their regulation of embryonic retinoic acid signaling (PMID:23937294)
• Loss of ZIC1 expression is associated with malignant pleural mesothelioma. (PMID:24457242)
• ZIC1 is frequently inactivated by promoter hypermethyaltion and functions as a tumor suppressor in thyroid cancer through modulating PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a. (PMID:24684457)
• aberrant methylation is an important mechanism for ZIC1 inactivation in Hepatocellular carcinoma (HCC). (PMID:24782033)
• ZIC1 might play a role in the development of Ovarian Cancer, and may be a therapeutic target in OC. (PMID:25953442)
• our results suggest that the Zic1 promoter methylation rate in plasma-derived DNA is of great significance for the early screening of gastric cancer and monitoring of tumorigenesis (PMID:26207911)
• Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability. (PMID:26340333)
• down-regulated expression of ZIC1 contributed to the inhibition of cell proliferation, and inhibited the growth of tumor (PMID:26670443)
• By unbiased genome-wide DNA methylation profiling and comprehensive stepwise verification and validation studies using in vitro and patient-derived samples, we identified 3 promising methylation markers (GHSR, SST, and ZIC1) associated with a 3q gain for the detection of cervical (pre)cancer (PMID:28119363)
• Two proposed mechanisms for Zic-mediated cerebellar developmental control have been documented: regulation of neuronal progenitor proliferation-differentiation and the patterning of the cerebellar primordium. Clinical studies have also revealed that ZIC1 gain of function mutations contribute to coronal craniosynostosis, a rare skull malformation. (PMID:29442326)
• Study demonstrate that ZIC1 plays a tumor suppressive role in breast cancer, by targeting surviving, significantly downregulating its expression. (PMID:29956756)
• A single factor induces neuronal differentiation to suppress glioma cell growth. (PMID:30264483)
• this severe brain malformation indicates that premature closure of sutures can be independent of the abnormal brain development in subjects with pathogenic variants in ZIC1. (PMID:30391508)
• Zic1 suppresses gastric cancer metastasis by regulating Wnt/beta-catenin signaling and epithelial-mesenchymal transition. (PMID:31909528)
• Roles and correlation of FOXA1 and ZIC1 in breast cancer. (PMID:32115254)
• LINC01419-mediated epigenetic silencing of ZIC1 promotes metastasis in hepatocellular carcinoma through the PI3K/Akt signaling pathway. (PMID:33772101)
• Transcriptional expression of ZICs as an independent indicator of survival in gliomas. (PMID:34475426)
• Mechanical-Stress-Related Epigenetic Regulation of ZIC1 Transcription Factor in the Etiology of Postmenopausal Osteoporosis. (PMID:35328378)
• Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes. (PMID:35628134)
• Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy. (PMID:35997131)
• ZIC1 Dictates Osteogenesis Versus Adipogenesis in Human Mesenchymal Progenitor Cells Via a Hedgehog Dependent Mechanism. (PMID:37317792)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zic1	ENSDARG00000015567
mus_musculus	Zic1	ENSMUSG00000032368
rattus_norvegicus	Zic1	ENSRNOG00000014644

Paralogs (14): ZIC2 (ENSG00000043355), ZXDC (ENSG00000070476), GLI2 (ENSG00000074047), GLI3 (ENSG00000106571), GLIS3 (ENSG00000107249), GLI1 (ENSG00000111087), GLIS2 (ENSG00000126603), AEBP2 (ENSG00000139154), ZIC5 (ENSG00000139800), ZIC3 (ENSG00000156925), GLIS1 (ENSG00000174332), ZIC4 (ENSG00000174963), ZXDA (ENSG00000198205), ZXDB (ENSG00000198455)

Protein

Protein identifiers

Zinc finger protein ZIC 1 — Q15915 (reviewed: Q15915)

Alternative names: Zinc finger protein 201, Zinc finger protein of the cerebellum 1

All UniProt accessions (2): Q15915, H7C5D8

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator. Involved in neurogenesis. Plays important roles in the early stage of organogenesis of the CNS, as well as during dorsal spinal cord development and maturation of the cerebellum. Involved in the spatial distribution of mossy fiber (MF) neurons within the pontine gray nucleus (PGN). Plays a role in the regulation of MF axon pathway choice. Promotes MF migration towards ipsilaterally-located cerebellar territories. May have a role in shear flow mechanotransduction in osteocytes. Retains nuclear GLI1 and GLI3 in the cytoplasm. Binds to the minimal GLI-consensus sequence 5’-TGGGTGGTC-3'.

Subunit / interactions. Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5). Interacts with GLI1; the interaction enhances transcription activation. Interacts with GLI2. Interacts with GLI3; the interaction enhances transcription activation.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. CNS. A high level expression is seen in the cerebellum. Detected in the nuclei of the cerebellar granule cell lineage from the progenitor cells of the external germinal layer to the postmigrated cells of the internal granular layer. Detected in medulloblastoma (26/29 cases), but not present in all other tumors examined.

Disease relevance. Craniosynostosis 6 (CRS6) [MIM:616602] A form of craniosynostosis, a primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. The disease is caused by variants affecting the gene represented in this entry. Structural brain anomalies with impaired intellectual development and craniosynostosis (BAIDCS) [MIM:618736] A disease characterized by microcephaly, agenesis of corpus callosum, abnormal conformation of the ventricles and posterior fossa, hypoplasia of both cerebellar hemispheres, colpocephaly, and partial absence of the cerebellar vermis with fusion of the cerebellar hemispheres. Intellectual development is moderately to severely impaired. Bicoronal synostosis, scoliosis, and tethered cord may be present. 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.

RefSeq proteins (1): NP_003403* (*=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 (14 total): zinc finger region 5, sequence variant 5, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15915-F1	55.77	0.08

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9834899	Specification of the neural plate border
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity

MSigDB gene sets: 374 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, chr3q24, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, LEE_NEURAL_CREST_STEM_CELL_DN, TAATAAT_MIR126, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_ADULT_BEHAVIOR, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, AREB6_01, AP2_Q3

GO Biological Process (18): regulation of transcription by RNA polymerase II (GO:0006357), pattern specification process (GO:0007389), central nervous system development (GO:0007417), brain development (GO:0007420), adult walking behavior (GO:0007628), regulation of smoothened signaling pathway (GO:0008589), gene expression (GO:0010467), spinal cord development (GO:0021510), hippocampus development (GO:0021766), olfactory bulb development (GO:0021772), cell differentiation (GO:0030154), positive regulation of protein import into nucleus (GO:0042307), inner ear morphogenesis (GO:0042472), positive regulation of DNA-templated transcription (GO:0045893), maintenance of cell number (GO:0098727), nervous system development (GO:0007399), forebrain development (GO:0030900), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (11): 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), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), 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
Gastrulation	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	4
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
system development	2
central nervous system development	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
multicellular organism development	1
multicellular organismal process	1
nervous system development	1
animal organ development	1
head development	1
adult locomotory behavior	1
walking behavior	1
smoothened signaling pathway	1
regulation of signal transduction	1
macromolecule biosynthetic process	1
pallium development	1
limbic system development	1
olfactory lobe development	1
cellular developmental process	1
protein import into nucleus	1
regulation of protein import into nucleus	1
positive regulation of nucleocytoplasmic transport	1
positive regulation of intracellular protein transport	1
positive regulation of protein localization to nucleus	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
developmental process	1
brain development	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1

Protein interactions and networks

STRING

2294 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZIC1	PAX3	P23760	777
ZIC1	CTNNB1	P35222	717
ZIC1	GLI1	P08151	696
ZIC1	ZPR1	O75312	684
ZIC1	FOXD3	Q9UJU5	679
ZIC1	LHX8	Q68G74	671
ZIC1	TMEM26	Q6ZUK4	669
ZIC1	MSX1	P28360	620
ZIC1	TBX6	O95947	612
ZIC1	TENM2	Q9NT68	605
ZIC1	PAX6	P26367	590
ZIC1	SOX10	P56693	579
ZIC1	UCP1	P25874	571
ZIC1	EN2	P19622	571
ZIC1	GBX2	P52951	566

IntAct

264 interactions, top by confidence:

A	B	Type	Score
ZIC1	BLZF1	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	BATF3	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	SMYD3	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	GAS2L3	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	AKAP8L	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	ZNF620	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
SMAD4	ZIC1	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	SMUG1	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	ANKRD10	psi-mi:“MI:0915”(physical association)	0.560
	ZIC1	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	ABHD11	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	ZIC1	psi-mi:“MI:0915”(physical association)	0.560
TBX19	ZIC1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (152): SDR9C7 (Affinity Capture-MS), PLBD1 (Affinity Capture-MS), GDPD3 (Affinity Capture-MS), CTSH (Affinity Capture-MS), S100A7 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), CPA4 (Affinity Capture-MS), PLA2G4E (Affinity Capture-MS), RNASE7 (Affinity Capture-MS), SERPINA3 (Affinity Capture-MS), SERPINB3 (Affinity Capture-MS), CTSV (Affinity Capture-MS), SERPINB1 (Affinity Capture-MS), CASP14 (Affinity Capture-MS)

ESM2 similar proteins: A0A455LJ99, A0A9P4XV22, A1C6L9, A1DH89, A2QCJ9, A5ABV9, B0XS89, B0XSK6, B0YDH7, B8NGC8, G4NB64, G5EB20, J9VX63, N4XMB0, O14335, O59958, O73689, O74252, O94130, O94131, O94166, P10071, P46684, Q00202, Q00203, Q01864, Q01981, Q05620, Q15915, Q4WJ81, Q4WXK4, Q4WY67, Q4X0Z3, Q52B93, Q5IS56, Q5XL24, Q61602, Q6DJQ6, Q7RVQ8, Q870A3

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

4 interactions.

A	Effect	B	Mechanism
ZIC1	up-regulates	GLI1	relocalization
ZIC1	up-regulates	GLI1
ZIC1	up-regulates	GLI3	relocalization
ZIC1	up-regulates	GLI3

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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
Keratinization	17	24.3×	6e-18

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	7
Uncertain significance	95
Likely benign	72
Benign	15

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
372161	NM_003412.4(ZIC1):c.1163C>A (p.Ser388Ter)	Pathogenic
372162	NM_003412.4(ZIC1):c.1165C>T (p.Gln389Ter)	Pathogenic
372163	NM_003412.4(ZIC1):c.1204G>T (p.Glu402Ter)	Pathogenic
372164	NM_003412.4(ZIC1):c.1198G>C (p.Gly400Arg)	Pathogenic
804366	NM_003412.4(ZIC1):c.1214_1215insCACCATCGT (p.Thr405_Pro406insThrIleVal)	Pathogenic
817963	NM_003412.4(ZIC1):c.1184_1194del (p.Pro395fs)	Pathogenic
1342557	NM_003412.4(ZIC1):c.1117C>A (p.His373Asn)	Likely pathogenic
2067436	NM_003412.4(ZIC1):c.1174C>T (p.Gln392Ter)	Likely pathogenic
3193556	NM_003412.4(ZIC1):c.1101C>A (p.Cys367Ter)	Likely pathogenic
3730857	NM_003412.4(ZIC1):c.1042G>A (p.Asp348Asn)	Likely pathogenic
809556	NM_003412.4(ZIC1):c.301C>A (p.Leu101Met)	Likely pathogenic
981197	NM_003412.4(ZIC1):c.1153G>T (p.Glu385Ter)	Likely pathogenic
985542	NM_003412.4(ZIC1):c.1130T>C (p.Leu377Pro)	Likely pathogenic

SpliceAI

1103 predictions. Top by Δscore:

Variant	Effect	Δscore
3:147402722:ACTT:A	donor_loss	1.0000
3:147402723:CTT:C	donor_loss	1.0000
3:147402724:TTAC:T	donor_loss	1.0000
3:147402725:TA:T	donor_loss	1.0000
3:147402726:A:AC	donor_gain	1.0000
3:147402726:A:C	donor_loss	1.0000
3:147402727:C:CA	donor_loss	1.0000
3:147402727:C:CC	donor_gain	1.0000
3:147402727:CTTGA:C	donor_gain	1.0000
3:147402729:TG:T	donor_gain	1.0000
3:147412505:A:AG	acceptor_gain	1.0000
3:147412505:ACTTT:A	acceptor_gain	1.0000
3:147412506:C:G	acceptor_gain	1.0000
3:147412509:T:A	acceptor_gain	1.0000
3:147412509:T:TA	acceptor_loss	1.0000
3:147412510:G:A	acceptor_gain	1.0000
3:147412513:A:AG	acceptor_gain	1.0000
3:147412513:ACCAG:A	acceptor_gain	1.0000
3:147412514:C:G	acceptor_gain	1.0000
3:147412516:A:AG	acceptor_gain	1.0000
3:147412516:AG:A	acceptor_gain	1.0000
3:147412516:AGG:A	acceptor_gain	1.0000
3:147412516:AGGG:A	acceptor_gain	1.0000
3:147412517:G:GT	acceptor_gain	1.0000
3:147412517:GG:G	acceptor_gain	1.0000
3:147412517:GGG:G	acceptor_gain	1.0000
3:147412517:GGGG:G	acceptor_gain	1.0000
3:147412517:GGGGA:G	acceptor_gain	1.0000
3:147412678:GAAG:G	donor_gain	1.0000
3:147412679:A:T	donor_gain	1.0000

AlphaMissense

2964 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:147410848:T:C	F246L	1.000
3:147410849:T:C	F246S	1.000
3:147410850:C:A	F246L	1.000
3:147410850:C:G	F246L	1.000
3:147410867:T:C	L252P	1.000
3:147410938:T:C	C276R	1.000
3:147410978:T:C	L289P	1.000
3:147410986:C:A	H292N	1.000
3:147410986:C:G	H292D	1.000
3:147410987:A:C	H292P	1.000
3:147410988:C:A	H292Q	1.000
3:147410988:C:G	H292Q	1.000
3:147410992:C:A	R294S	1.000
3:147410993:G:C	R294P	1.000
3:147410998:C:G	H296D	1.000
3:147411000:C:A	H296Q	1.000
3:147411000:C:G	H296Q	1.000
3:147411016:T:C	F302L	1.000
3:147411018:T:A	F302L	1.000
3:147411018:T:G	F302L	1.000
3:147411022:T:A	C304S	1.000
3:147411022:T:C	C304R	1.000
3:147411023:G:A	C304Y	1.000
3:147411023:G:C	C304S	1.000
3:147411024:C:G	C304W	1.000
3:147411037:T:C	C309R	1.000
3:147411039:T:G	C309W	1.000
3:147411049:T:C	F313L	1.000
3:147411050:T:C	F313S	1.000
3:147411050:T:G	F313C	1.000

dbSNP variants (sampled 300 via entrez): RS1000275177 (3:147416368 A>G), RS1000680641 (3:147411718 G>C), RS1001199267 (3:147411292 G>A), RS1001355370 (3:147408891 C>T), RS1001403635 (3:147415468 C>T), RS1001504658 (3:147415719 C>T), RS1001525705 (3:147409548 C>A,T), RS1001631190 (3:147409870 G>A,T), RS1001817138 (3:147416285 T>A), RS1001868750 (3:147408647 C>G,T), RS1002184409 (3:147416021 G>A,T), RS1002410153 (3:147416926 G>A), RS1002466622 (3:147409937 G>A,T), RS1002901211 (3:147407775 T>A), RS1002955352 (3:147407461 T>G)

Disease associations

OMIM: gene MIM:600470 | disease phenotypes: MIM:618736, MIM:616602

GenCC curated gene-disease

Disease	Classification	Inheritance
craniosynostosis 6	Definitive	Autosomal dominant
structural brain anomalies with impaired intellectual development and craniosynostosis	Strong	Autosomal dominant
isolated plagiocephaly	Supportive	Autosomal dominant
isolated brachycephaly	Supportive	Autosomal dominant
isolated oxycephaly	Supportive	Autosomal dominant
Dandy-Walker syndrome	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
craniosynostosis 6	Definitive	AD

Mondo (6): structural brain anomalies with impaired intellectual development and craniosynostosis (MONDO:0032892), craniosynostosis 6 (MONDO:0014705), Dandy-Walker syndrome (MONDO:0009072), (MONDO:0018113), (MONDO:0018114), isolated oxycephaly (MONDO:0018971)

Orphanet (1): Craniosynostosis-skeletal and cerebellar anomalies-learning disabilities syndrome (Orphanet:672985)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000270	Delayed cranial suture closure
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000337	Broad forehead
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000609	Optic nerve hypoplasia
HP:0000729	Autistic behavior
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001274	Agenesis of corpus callosum
HP:0001305	Dandy-Walker malformation
HP:0001357	Plagiocephaly
HP:0001363	Craniosynostosis
HP:0001476	Delayed closure of the anterior fontanelle
HP:0002516	Increased intracranial pressure
HP:0002650	Scoliosis

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000269_10	Multiple sclerosis	8.000000e-06
GCST003518_3	Daytime sleep phenotypes	2.000000e-06
GCST003518_43	Daytime sleep phenotypes	1.000000e-06
GCST003989_43	Chin dimples	4.000000e-09
GCST003996_20	Monobrow	2.000000e-09
GCST010002_442	Refractive error	8.000000e-12
GCST010699_2	Brain morphology (min-P)	3.000000e-11
GCST010701_124	Cortical surface area (MOSTest)	7.000000e-11
GCST010702_73	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_88	Brain morphology (MOSTest)	5.000000e-87
GCST010988_118	Adult body size	9.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0007906	synophrys measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	7
trichostatin A	increases expression, decreases expression, affects cotreatment	3
Benzo(a)pyrene	affects methylation, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
decabromobiphenyl ether	increases expression	1
terbufos	increases methylation	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
tetrabromobisphenol A	increases expression	1
ferrous chloride	decreases expression	1
tetrachlorodian	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
incobotulinumtoxinA	increases expression	1
Panobinostat	affects cotreatment, affects expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, affects expression	1
Coumestrol	decreases expression	1
Cyclophosphamide	affects response to substance	1
Fonofos	increases methylation	1
Endosulfan	decreases expression	1
Nickel	decreases expression	1
Parathion	increases methylation	1
Silicon Dioxide	increases 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_A8C3	SEES3-1V human ZIC1, clone1	Embryonic stem cell	Male
CVCL_A8C4	SEES3-1V human ZIC1, clone2	Embryonic stem cell	Male
CVCL_A8C5	SEES3-1V human ZIC1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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