ZIC5

Summary

ZIC5 (Zic family zinc finger 5, HGNC:20322) is a protein-coding gene on chromosome 13q32.3, encoding Zinc finger protein ZIC 5 (Q96T25). Essential for neural crest development, converting cells from an epidermal fate to a neural crest cell fate.

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. The encoded protein may act as a transcriptional repressor. Studies in mouse and Xenopus support a role for this gene in neural crest development. Elevated expression of this gene has been observed in various human cancers and may contribute to cancer progression. This gene is closely linked to a related family member on chromosome 13.

Source: NCBI Gene 85416 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 158 total
• MANE Select transcript: NM_033132

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20322
Approved symbol	ZIC5
Name	Zic family zinc finger 5
Location	13q32.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000139800
Ensembl biotype	protein_coding
OMIM	617896
Entrez	85416

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000267294

RefSeq mRNA: 1 — MANE Select: NM_033132 NM_033132

CCDS: CCDS9494

Canonical transcript exons

ENST00000267294 — 2 exons

Exon	Start	End
ENSE00001623491	99970127	99971767
ENSE00001685523	99962964	99965819

Expression profiles

Bgee: expression breadth broad, 57 present calls, max score 88.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3909 / max 105.4742, expressed in 147 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138041	0.1844	92
138040	0.1307	47
138037	0.0432	14
138039	0.0200	5
138038	0.0128	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	88.25	gold quality
cerebellar hemisphere	UBERON:0002245	88.11	gold quality
cerebellar cortex	UBERON:0002129	88.04	gold quality
ventricular zone	UBERON:0003053	86.86	gold quality
cerebellum	UBERON:0002037	86.02	gold quality
ganglionic eminence	UBERON:0004023	77.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.01	gold quality
sural nerve	UBERON:0015488	71.77	gold quality
cerebellar vermis	UBERON:0004720	68.55	gold quality
right frontal lobe	UBERON:0002810	64.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	64.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	63.77	gold quality
anterior cingulate cortex	UBERON:0009835	62.44	gold quality
amygdala	UBERON:0001876	61.64	gold quality
prefrontal cortex	UBERON:0000451	60.17	gold quality
nasal cavity epithelium	UBERON:0005384	59.32	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	59.08	gold quality
neocortex	UBERON:0001950	59.04	gold quality
myocardium	UBERON:0002349	58.93	gold quality
frontal cortex	UBERON:0001870	58.20	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	57.57	gold quality
right testis	UBERON:0004534	57.19	gold quality
cerebral cortex	UBERON:0000956	57.09	gold quality
brain	UBERON:0000955	57.06	gold quality
spinal cord	UBERON:0002240	56.03	gold quality
testis	UBERON:0000473	55.92	gold quality
Ammon’s horn	UBERON:0001954	55.78	gold quality
left testis	UBERON:0004533	55.75	gold quality
cortical plate	UBERON:0005343	55.58	silver quality
putamen	UBERON:0001874	54.79	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.12
E-MTAB-6058	no	195.91

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA1584.1	ZIC5	More than 3 adjacent zinc fingers
MA1584.2	ZIC5	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:23354101

Upstream regulators (CollecTRI, top): TCF7L1

miRNA regulators (miRDB)

146 targeting ZIC5, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3658	99.96	73.87	4379

Literature-anchored findings (GeneRIF, showing 13)

• ZIC1, ZIC2, and ZIC5 may have roles in meningiomas (PMID:20199689)
• the smallest 13q deletion associated to DWM allows further narrowing of the previously established critical region for this brain malformation to 13q32.2-32.3. Among the few genes of the deleted region, ZIC2 and ZIC5 seem the most plausible candidates. (PMID:20683983)
• ZIC5 is highly upregulated in non-small cell lung cancer tumor tissues and may act as an oncogene by influencing CCNB1 and CDK1 complex expression (PMID:27663664)
• ZIC5 positively regulated the proliferation, migration, and survival of prostate colorectal cancer cells (PMID:29024195)
• hsa_circ_0007534 serves as an oncogene in glioma via promoting ZIC5 expression by repressing miR-761 availability. (PMID:29605301)
• The study reveals a novel mechanism of ZIC5/beta-catenin that mediates the invasion and metastasis of HCC and ZIC5 serves as a novel indicator for prognosis of hepatocellular carcinoma (HCC) patients. (PMID:30086882)
• Interfering Wnt/-catenin-Zic5 axis-regulated aerobic glycolysis represents a potentially effective strategy to selectively target colon cancer cells. (PMID:31392276)
• SP1-mediated upregulation of lncRNA SNHG4 functions as a ceRNA for miR-377 to facilitate prostate cancer progression through regulation of ZIC5. (PMID:31608997)
• Transcriptional expression of ZICs as an independent indicator of survival in gliomas. (PMID:34475426)
• LINC01116 Regulates the Proliferation and Apoptosis of Nucleus Pulposus Cells through miR-9-5p-mediated ZIC5 and the Wnt Pathway and Affects the Progression of Intervertebral Disc Degeneration. (PMID:35927800)
• ZIC5 promotes aggressiveness and cancer stemness in cervical squamous cell carcinoma. (PMID:36495760)
• MicroRNA-101-3p inhibits nasopharyngeal carcinoma cell proliferation and cisplatin resistance through ZIC5 down-regulation by targeting SOX2. (PMID:36752150)
• Research progress of ZIC5 for tumor metastasis. (PMID:38747731)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zic5	ENSDARG00000016022
mus_musculus	Zic5	ENSMUSG00000041703
rattus_norvegicus	Zic5	ENSRNOG00000014358

Paralogs (14): ZIC2 (ENSG00000043355), ZXDC (ENSG00000070476), GLI2 (ENSG00000074047), GLI3 (ENSG00000106571), GLIS3 (ENSG00000107249), GLI1 (ENSG00000111087), GLIS2 (ENSG00000126603), AEBP2 (ENSG00000139154), ZIC1 (ENSG00000152977), ZIC3 (ENSG00000156925), GLIS1 (ENSG00000174332), ZIC4 (ENSG00000174963), ZXDA (ENSG00000198205), ZXDB (ENSG00000198455)

Protein

Protein identifiers

Zinc finger protein ZIC 5 — Q96T25 (reviewed: Q96T25)

Alternative names: Zinc finger protein of the cerebellum 5

All UniProt accessions (1): Q96T25

UniProt curated annotations — full annotation on UniProt →

Function. Essential for neural crest development, converting cells from an epidermal fate to a neural crest cell fate. Binds to DNA.

Subcellular location. Nucleus.

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

RefSeq proteins (1): NP_149123* (*=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 (20 total): region of interest 6, zinc finger region 4, compositionally biased region 4, modified residue 3, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96T25-F1	52.58	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 (3): 554, 558, 576

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 96 (showing top): GGGTGGRR_PAX4_03, FREAC3_01, NF1_Q6_01, HFH4_01, AACTTT_UNKNOWN, DBP_Q6, NKX3A_01, FOX_Q2, chr13q32, TGGAAA_NFAT_Q4_01, TCCCRNNRTGC_UNKNOWN, HNF3_Q6, GEORGES_TARGETS_OF_MIR192_AND_MIR215, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), cell differentiation (GO:0030154), nervous system development (GO:0007399)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), metal ion binding (GO:0046872)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
nervous system development	1
cellular developmental process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transition metal ion binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
nucleic acid binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

852 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZIC5	RNF113B	Q8IZP6	447
ZIC5	AKAP8L	Q9ULX6	403
ZIC5	OTX2	P32243	387
ZIC5	CPPED1	Q9BRF8	356
ZIC5	DDX42	Q86XP3	355
ZIC5	ZIC2	O95409	351
ZIC5	FOXD3	Q9UJU5	339
ZIC5	DOCK9	Q9BZ29	330
ZIC5	PAX6	P26367	309
ZIC5	ALX3	O95076	307
ZIC5	HIPK3	Q9H422	306
ZIC5	NR2E1	Q9Y466	299
ZIC5	KLHL2	O95198	298
ZIC5	TFCP2L1	Q9NZI6	290
ZIC5	DMBX1	Q8NFW5	289
ZIC5	RNPEP	Q9H4A4	289

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ZIC5	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (9): ZIC5 (Affinity Capture-MS), ZIC5 (Affinity Capture-RNA), ZIC5 (Affinity Capture-MS), ZIC5 (Affinity Capture-MS), ZIC5 (Protein-RNA), ZIC5 (Proximity Label-MS), ZIC5 (Proximity Label-MS), ZIC5 (Proximity Label-MS), ZIC5 (Proximity Label-MS)

ESM2 similar proteins: A0A8V0YY16, A2T7H5, A8MTJ6, B5RHS5, D3Z120, O00358, O35392, O35767, O54743, O60548, O88470, P09631, P18111, P23813, P31277, P42582, P47902, P52952, P58012, P78415, P79772, P81067, P84550, P84551, Q12947, Q12948, Q12952, Q16676, Q3I5G5, Q3Y598, Q4VUF1, Q61060, Q61345, Q61572, Q61850, Q62424, Q63244, Q63246, Q6VFT5, Q6VFT6

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	135
Likely benign	15
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

395 predictions. Top by Δscore:

Variant	Effect	Δscore
13:99965816:TCCC:T	acceptor_gain	1.0000
13:99965817:CCC:C	acceptor_gain	1.0000
13:99965817:CCCC:C	acceptor_gain	1.0000
13:99965818:CC:C	acceptor_gain	1.0000
13:99965818:CCC:C	acceptor_gain	1.0000
13:99965819:CC:C	acceptor_gain	1.0000
13:99965820:C:A	acceptor_loss	1.0000
13:99965820:C:CC	acceptor_gain	1.0000
13:99965821:T:A	acceptor_loss	1.0000
13:99965661:T:TA	donor_gain	0.9900
13:99965815:TTCCC:T	acceptor_gain	0.9900
13:99968961:T:TA	donor_gain	0.9800
13:99969025:A:C	donor_gain	0.9800
13:99969738:T:TA	donor_gain	0.9800
13:99969739:C:A	donor_gain	0.9800
13:99969783:T:TA	donor_gain	0.9800
13:99969771:T:TA	donor_gain	0.9700
13:99965823:C:CT	acceptor_gain	0.9600
13:99969024:A:AC	donor_gain	0.9600
13:99970122:CCCA:C	donor_loss	0.9600
13:99970123:CCA:C	donor_loss	0.9600
13:99970124:CA:C	donor_loss	0.9600
13:99970125:A:AG	donor_loss	0.9600
13:99970126:C:T	donor_loss	0.9600
13:99965824:A:T	acceptor_gain	0.9500
13:99967986:TGCGG:T	donor_gain	0.9500
13:99967574:TCATC:T	donor_gain	0.9400
13:99967575:CATCC:C	donor_gain	0.9400
13:99967576:ATCCA:A	donor_gain	0.9400
13:99969020:A:AC	donor_gain	0.9400

AlphaMissense

4286 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:99965685:A:C	Y562D	1.000
13:99965710:G:C	C553W	1.000
13:99965711:C:G	C553S	1.000
13:99965711:C:T	C553Y	1.000
13:99965712:A:G	C553R	1.000
13:99965712:A:T	C553S	1.000
13:99965773:A:C	F532L	1.000
13:99965773:A:T	F532L	1.000
13:99965774:A:G	F532S	1.000
13:99965775:A:G	F532L	1.000
13:99965786:C:G	C528S	1.000
13:99965786:C:T	C528Y	1.000
13:99965787:A:G	C528R	1.000
13:99965787:A:T	C528S	1.000
13:99965801:C:G	C523S	1.000
13:99965802:A:G	C523R	1.000
13:99965802:A:T	C523S	1.000
13:99965806:G:C	F521L	1.000
13:99965806:G:T	F521L	1.000
13:99965808:A:G	F521L	1.000
13:99970138:C:G	R513P	1.000
13:99970139:G:T	R513S	1.000
13:99970145:G:C	H511D	1.000
13:99970153:A:G	L508P	1.000
13:99970170:G:C	F502L	1.000
13:99970170:G:T	F502L	1.000
13:99970171:A:G	F502S	1.000
13:99970172:A:G	F502L	1.000
13:99970197:G:C	C493W	1.000
13:99970198:C:G	C493S	1.000

dbSNP variants (sampled 300 via entrez): RS1000539945 (13:99972288 G>A), RS1000611457 (13:99971341 G>A), RS1001017851 (13:99967940 T>C), RS1001131290 (13:99967117 A>C), RS1001690833 (13:99964642 G>A), RS1002024603 (13:99966266 G>A), RS1002143123 (13:99966428 A>G), RS1002382074 (13:99966103 T>A,C), RS1002404782 (13:99972469 T>A), RS1002708808 (13:99971563 C>T), RS1002715738 (13:99964574 A>G), RS1002747896 (13:99963500 T>C), RS1002783617 (13:99972649 C>T), RS1003607899 (13:99969498 C>T), RS1003962243 (13:99969303 A>G)

Disease associations

OMIM: gene MIM:617896 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002617_3	Hyperopia	7.000000e-06
GCST007327_130	Smoking status (ever vs never smokers)	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression	4
mercuric bromide	decreases expression, affects cotreatment	2
Estradiol	increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tretinoin	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
methylmercuric chloride	decreases expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Microplastics	decreases expression, increases abundance	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Caffeine	decreases phosphorylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Polystyrenes	decreases expression, increases abundance	1
Silver	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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