ZIC2

Summary

ZIC2 (Zic family zinc finger 2, HGNC:12873) is a protein-coding gene on chromosome 13q32.3, encoding Zinc finger protein ZIC 2 (O95409). Acts as a transcriptional activator or repressor. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This protein functions as a transcriptional repressor and may regulate tissue specific expression of dopamine receptor D1. Expansion of an alanine repeat in the C-terminus of the encoded protein and other mutations in this gene cause holoprosencephaly type 5. Holoprosencephaly is the most common structural anomaly of the human brain. A polyhistidine tract polymorphism in this gene may be associated with increased risk of neural tube defects. This gene is closely linked to a gene encoding zinc finger protein of the cerebellum 5, a related family member on chromosome 13.

Source: NCBI Gene 7546 — RefSeq curated summary.

At a glance

• Gene–disease (curated): holoprosencephaly 5 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 480 total — 32 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 142
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_007129

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12873
Approved symbol	ZIC2
Name	Zic family zinc finger 2
Location	13q32.3
Locus type	gene with protein product
Status	Approved
Aliases	HPE5
Ensembl gene	ENSG00000043355
Ensembl biotype	protein_coding
OMIM	603073
Entrez	7546

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000376335, ENST00000468291, ENST00000477213, ENST00000481565, ENST00000490085

RefSeq mRNA: 1 — MANE Select: NM_007129 NM_007129

CCDS: CCDS9495

Canonical transcript exons

ENST00000376335 — 3 exons

Exon	Start	End
ENSE00001470245	99981784	99983139
ENSE00001758046	99985323	99986765
ENSE00003565692	99984946	99985109

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 98.41.

FANTOM5 (CAGE): breadth broad, TPM avg 14.9294 / max 608.8736, expressed in 685 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135853	7.6077	492
135852	2.1626	479
135864	1.9023	372
135856	1.5514	504
135865	0.4725	163
135854	0.4227	238
135855	0.2110	115
135861	0.1230	55
135862	0.1188	52
135858	0.1058	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar cortex	UBERON:0002129	98.41	gold quality
cerebellar hemisphere	UBERON:0002245	98.40	gold quality
cerebellum	UBERON:0002037	97.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.97	gold quality
pons	UBERON:0000988	97.41	gold quality
cerebellar vermis	UBERON:0004720	96.23	gold quality
adult organism	UBERON:0007023	93.71	gold quality
ventricular zone	UBERON:0003053	90.97	gold quality
trigeminal ganglion	UBERON:0001675	90.59	gold quality
endothelial cell	CL:0000115	84.30	gold quality
lateral nuclear group of thalamus	UBERON:0002736	83.31	gold quality
ganglionic eminence	UBERON:0004023	82.54	gold quality
paraflocculus	UBERON:0005351	82.44	gold quality
right frontal lobe	UBERON:0002810	81.49	gold quality
Ammon’s horn	UBERON:0001954	80.92	gold quality
postcentral gyrus	UBERON:0002581	80.56	gold quality
Brodmann (1909) area 23	UBERON:0013554	80.46	gold quality
superior frontal gyrus	UBERON:0002661	80.06	gold quality
entorhinal cortex	UBERON:0002728	79.95	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.98	silver quality
cerebral cortex	UBERON:0000956	78.58	gold quality
temporal lobe	UBERON:0001871	78.56	gold quality
parietal lobe	UBERON:0001872	78.53	gold quality
middle temporal gyrus	UBERON:0002771	78.04	gold quality
frontal cortex	UBERON:0001870	78.03	gold quality
neocortex	UBERON:0001950	78.00	gold quality
primary visual cortex	UBERON:0002436	78.00	gold quality
amygdala	UBERON:0001876	77.88	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.46	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	940.65
E-GEOD-75140	yes	761.41
E-MTAB-10018	no	342.11
E-MTAB-6524	no	188.39
E-GEOD-99795	no	19.40
E-ANND-3	no	1.63

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
APOE	Unknown
CAMK2A	Unknown
CAT
CDKN2A
DRD1	Unknown
SLC13A4	Unknown
SLC6A4	Activation
SPTA1
TCF4	Repression
TPM1

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

118 targeting ZIC2, 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-4262	100.00	73.26	3931
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Sample was too small to reach definitive conclusions, but the evidence is sufficiently intriguing to encourage further research. (PMID:11857562)
• Holoprosencephaly in monosomy 13q may be related to ZIC2 gene loss of function. (PMID:11910512)
• Zic2 is an evolutionarily conserved determinant of retinal ganglion cells that project ipsilaterally (PMID:13678579)
• Four novel ZIC2 mutations found in a cohort of Holoprosencephaly patinets. (PMID:15221788)
• The C-terminal alanine-tract of ZIC2 influences the strength of DNA binding and alters transcriptional activity in a promoter-specific manner (PMID:15590697)
• Forms two different complexes with DNA-dependent protein kinase, poly(ADP-ribose) polymerase, and RNA helicase A; all the components interacted directly with Zic2 protein (PMID:17251188)
• This transcription factor regulates the expression of EphB1 in RGCs and also suggest the existence of an additional EphB1-independent pathway controlled by Zic2 that contributes to retinal axon divergence at the midline. (PMID:18417618)
• ZIC2, SPRY2, and GPC5 genes are candidate genes suspected to explain the malformations associated with cerebral anomalies in the hypothesis of a contiguous gene syndrome in 13q deletion syndrome (PMID:19022413)
• Loss-of-function as the likely pathogenetic mechanism common to most, if not all, of ZIC2 mutations in holoprosencephaly. (PMID:19177455)
• ZIC2 expression was associated with the histopathologic types of oral squamous cell carcinoma (PMID:19784848)
• Holoprosencephaly due to ZIC2 mutations is distinct from that due to mutations in other genes. (PMID:19955556)
• ZIC1, ZIC2, and ZIC5 may have roles in meningiomas (PMID:20199689)
• screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3 (PMID:20531442)
• 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)
• mutation of ZIC2 is a rare cause of, or contributor to, RES associated with HPE. (PMID:21638761)
• Our findings suggest that Zic2 is a positive modulator increasing Gli1 transcriptional and oncogenic activity by retaining Gli1 in the nucleus of cervical cancer cells. (PMID:21661123)
• role for ZIC2 as a transcriptional regulator of the beta-catenin.TCF4 complex. (PMID:21908606)
• Brain malformations, including neuronal migration defects, predominated in individuals with ZIC2 mutations. (PMID:21940735)
• Mutations in ZIC2 is associated with holoprosencephaly. (PMID:22310223)
• ZIC2, a transcription factor related to the sonic hedgehog pathway, is a strong discriminant between MAL and LMP tumors: it may be a major determinant of outcome of EOTs. (PMID:22733541)
• The c.1401_1406dup (p.Ala469_470dup) or alanine tract expansion to 17 residues) in the ZIC2 gene are likely to be medically significant for holoprosencephaly in a Brazilian cohort. (PMID:22847929)
• A high level of sequence variation in the 3’UTR of ZIC2 may be associated with holoprosencephaly. (PMID:22859937)
• ZIC2 and RASGRF1 are susceptibility genes, not only for common myopia, but also for high myopia. (PMID:24150758)
• Mutational screening for HPE genes revealed the occurrence of a frameshift mutation in the ZIC2 gene. (PMID:24677696)
• Data show that Zinc finger protein ZIC 2 (ZIC2) is indispensable in the regulation of pancreatic ductal adenocarcinoma (PDAC) cell apoptosis. (PMID:26318045)
• ZIC2 acts upstream of OCT4 and recruits the nuclear remodeling factor complex to the OCT4 promoter, initiating OCT4 activation. ZIC2 levels positively correlated to the clinicopathological stages of HCC patients. (PMID:26426078)
• Together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and Zic2 also controls the foxA2 expression during Xenopus development. These findings reveal a new mechanism of NODAL signal transduction in the mammalian node and provide the first molecular explanation of how ZIC2 loss-of-function precipitates Holoprosencephaly (HPE (PMID:27466203)
• miR-1271/Zic2/PAK4 axis plays an important role in hepatocellular carcinoma progression. (PMID:28577975)
• the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. (PMID:29442327)
• ZIC2 regulates laterality of cardiovascular system. A subset of holoprosencephaly cases with ZIC2 mutation also exhibit heterotaxy. Mouse mutant shows right isomerism indicating lack of left-sided Nodal signalling in the embryo. Mechanistic studies in vitro indicate that ZIC2 is required for Nodal expression at the embryonic node and binds to the Nodal HBE enhancer in epiblast. (PMID:29992973)
• miR-1284 suppressed the proliferation, migration, and invasion of breast cancer cells via targeting ZIC2. (PMID:30075825)
• MiR12715p inhibited the progression of AML by targeting ZIC2. (PMID:30483794)
• Results identified loss of ZIC2 expression following DNA hypomethylation as a promising prognostic biomarker for prostate cancer. (PMID:31640781)
• MicroRNA-129-5p suppresses nasopharyngeal carcinoma lymphangiogenesis and lymph node metastasis by targeting ZIC2. (PMID:31884576)
• ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer. (PMID:32064600)
• The tumor-suppressive role of microRNA-873 in nasopharyngeal carcinoma correlates with downregulation of ZIC2 and inhibition of AKT signaling pathway. (PMID:32555352)
• Correlation of zinc finger protein 2, a prognostic biomarker, with immune infiltrates in liver cancer. (PMID:33439969)
• De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family. (PMID:33557041)
• Multilevel regulation of Wnt signaling by Zic2 in colon cancer due to mutation of beta-catenin. (PMID:34099631)
• Downregulation of LINC00665 suppresses the progression of lung adenocarcinoma via regulating miR-181c-5p/ZIC2 axis. (PMID:34232917)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	zic2a	ENSDARG00000015554
danio_rerio	zic2b	ENSDARG00000037178
mus_musculus	Zic2	ENSMUSG00000061524
rattus_norvegicus	Zic2	ENSRNOG00000054879

Paralogs (14): ZXDC (ENSG00000070476), GLI2 (ENSG00000074047), GLI3 (ENSG00000106571), GLIS3 (ENSG00000107249), GLI1 (ENSG00000111087), GLIS2 (ENSG00000126603), AEBP2 (ENSG00000139154), ZIC5 (ENSG00000139800), ZIC1 (ENSG00000152977), ZIC3 (ENSG00000156925), GLIS1 (ENSG00000174332), ZIC4 (ENSG00000174963), ZXDA (ENSG00000198205), ZXDB (ENSG00000198455)

Protein

Protein identifiers

Zinc finger protein ZIC 2 — O95409 (reviewed: O95409)

Alternative names: Zinc finger protein of the cerebellum 2

All UniProt accessions (1): O95409

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator or repressor. Plays important roles in the early stage of organogenesis of the CNS. Activates the transcription of the serotonin transporter SERT in uncrossed ipsilateral retinal ganglion cells (iRGCs) to refine eye-specific projections in primary visual targets. Its transcriptional activity is repressed by MDFIC. Involved in the formation of the ipsilateral retinal projection at the optic chiasm midline. Drives the expression of EPHB1 on ipsilaterally projecting growth cones. Binds to the minimal GLI-consensus sequence 5’-TGGGTGGTC-3’. Associates to the basal SERT promoter region from ventrotemporal retinal segments of retinal embryos.

Subunit / interactions. Interacts with RNF180. 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 GLI1 and GLI2. Interacts (via C2H2-type domain 3) with DHX9.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Phosphorylated. Ubiquitinated by RNF180, leading to its degradation.

Disease relevance. Holoprosencephaly 5 (HPE5) [MIM:609637] A form of holoprosencephaly, a structural anomaly of the brain in which the developing forebrain fails to correctly separate into right and left hemispheres. It is a genetically and clinically heterogeneous disorder with a wide spectrum of severity, ranging from alobar holoprosencephaly with severe facial abnormalities, such as cyclopia and proboscis, to mild forms that include lobar or microform holoprosencephaly, without cerebral malformations and with mild craniofacial defects. HPE5 inheritance is autosomal dominant. 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.

Polymorphism. The poly-His region between amino acids 231-239 of ZIC2 is polymorphic and the number of His can vary from 8 to 12.

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

RefSeq proteins (1): NP_009060* (*=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 (40 total): sequence variant 24, zinc finger region 5, compositionally biased region 3, region of interest 3, modified residue 2, chain 1, cross-link 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95409-F1	51.36	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): 191, 199, 253

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9823739	Formation of the anterior neural plate

MSigDB gene sets: 461 (showing top): FXR_IR1_Q6, MODULE_52, PAX4_01, KEGG_HEDGEHOG_SIGNALING_PATHWAY, PEREZ_TP63_TARGETS, MODULE_45, HNF1_Q6, MODULE_16, GGGTGGRR_PAX4_03, PATIL_LIVER_CANCER, MODULE_66, MODULE_118, WATANABE_COLON_CANCER_MSI_VS_MSS_UP, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, SOX9_B1

GO Biological Process (9): regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), brain development (GO:0007420), visual perception (GO:0007601), cell differentiation (GO:0030154), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), obsolete positive regulation of DNA-binding transcription factor activity (GO:0051091), nervous system development (GO:0007399)

GO Molecular Function (9): 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 (GO:0003677), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), chromatin DNA binding (GO:0031490), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gastrulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
system development	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
nervous system development	1
central nervous system development	1
animal organ development	1
head development	1
sensory perception of light stimulus	1
cellular developmental process	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic 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
nucleic acid binding	1
transcription regulator activity	1
transition metal ion binding	1
DNA binding	1
chromatin binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1674 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZIC2	SIX3	O95343	934
ZIC2	DISP1	Q96F81	919
ZIC2	SHH	Q15465	857
ZIC2	EPHB1	P54762	835
ZIC2	FOXA2	Q9Y261	747
ZIC2	ISL2	Q96A47	742
ZIC2	GAS1	P54826	727
ZIC2	SMAD2	Q15796	657
ZIC2	PTCH1	Q13635	632
ZIC2	POU3F1	Q03052	609
ZIC2	EFNB2	P52799	602
ZIC2	NRCAM	Q92823	598
ZIC2	HOXA13	P31271	596
ZIC2	OTX2	P32243	585
ZIC2	CTNNB1	P35222	581

IntAct

19 interactions, top by confidence:

A	B	Type	Score
ZIC2	EFHD1	psi-mi:“MI:0915”(physical association)	0.560
NAGK	ZBTB43	psi-mi:“MI:0914”(association)	0.530
CHRNA9	CHEK1	psi-mi:“MI:0914”(association)	0.530
PRKDC	ZIC2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ZIC2		psi-mi:“MI:0915”(physical association)	0.370
TEAD2	DDX39A	psi-mi:“MI:0914”(association)	0.350
AHCYL2	AHCYL1	psi-mi:“MI:0914”(association)	0.350
ARRDC3	ESYT2	psi-mi:“MI:0914”(association)	0.350
FBLN5	ZNF320	psi-mi:“MI:0914”(association)	0.350
PDE3A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
EFNB1	KRBA1	psi-mi:“MI:0914”(association)	0.350
ARIH1	PHGDH	psi-mi:“MI:0914”(association)	0.350
TECTA	ZBTB43	psi-mi:“MI:0914”(association)	0.350
KCTD12	DUSP11	psi-mi:“MI:0914”(association)	0.350
ZIC2	EEF1A2	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): ZIC2 (Affinity Capture-MS), ZIC2 (Proximity Label-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-MS), ZIC2 (Affinity Capture-RNA), GLI1 (Affinity Capture-Western)

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
RNF180	“down-regulates quantity by destabilization”	ZIC2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	19
Uncertain significance	243
Likely benign	156
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073377	NM_007129.5(ZIC2):c.973C>T (p.Arg325Cys)	Pathogenic
1180672	NM_007129.5(ZIC2):c.1182_1183dup (p.Cys395fs)	Pathogenic
1435952	NM_007129.5(ZIC2):c.1156del (p.Val386fs)	Pathogenic
1994794	NM_007129.5(ZIC2):c.1199_1207del (p.Lys400_Tyr402del)	Pathogenic
2023461	NM_007129.5(ZIC2):c.911G>A (p.Trp304Ter)	Pathogenic
2034810	NM_007129.5(ZIC2):c.722del (p.Gly241fs)	Pathogenic
2232044	NM_007129.5(ZIC2):c.85_86insGGGGGGGGGG (p.Ala29fs)	Pathogenic
2431203	NM_007129.5(ZIC2):c.651del (p.Met217fs)	Pathogenic
2760100	NM_007129.5(ZIC2):c.773G>A (p.Cys258Tyr)	Pathogenic
280364	NM_007129.5(ZIC2):c.1097dup (p.Phe367fs)	Pathogenic
30298	NM_007129.5(ZIC2):c.397_403del (p.Gly133fs)	Pathogenic
3657484	NM_007129.5(ZIC2):c.452C>A (p.Ser151Ter)	Pathogenic
3778458	NM_007129.5(ZIC2):c.106C>T (p.Gln36Ter)	Pathogenic
397654	NM_007129.5(ZIC2):c.1097_1098del (p.Glu366fs)	Pathogenic
397655	NM_007129.5(ZIC2):c.793C>T (p.Gln265Ter)	Pathogenic
397656	NM_007129.5(ZIC2):c.1095_1096del (p.Cys365_Glu366delinsTer)	Pathogenic
397658	NM_007129.3:c.1148_1464del	Pathogenic
419833	NM_007129.5(ZIC2):c.725_728del (p.Ala242fs)	Pathogenic
437335	NM_007129.5(ZIC2):c.1085_1131del (p.Pro362fs)	Pathogenic
450157	NM_007129.5(ZIC2):c.637C>T (p.Gln213Ter)	Pathogenic
451180	NM_007129.5(ZIC2):c.494dup (p.His166fs)	Pathogenic
468364	NM_007129.5(ZIC2):c.1076-2A>T	Pathogenic
545578	NM_007129.5(ZIC2):c.321del (p.Tyr108fs)	Pathogenic
65487	NM_007129.5(ZIC2):c.936del (p.Lys312fs)	Pathogenic
65492	NM_007129.5(ZIC2):c.1091_1092del (p.Gln364fs)	Pathogenic
659143	NM_007129.5(ZIC2):c.1215del (p.Ser406fs)	Pathogenic
6637	NM_007129.4(ZIC2):c.177_178ins56	Pathogenic
6638	NM_007129.5(ZIC2):c.1318dup (p.Leu440fs)	Pathogenic
6640	NM_007129.5(ZIC2):c.1042_1048del (p.Glu348fs)	Pathogenic
6641	NM_007129.5(ZIC2):c.857_858del (p.His286fs)	Pathogenic

SpliceAI

328 predictions. Top by Δscore:

Variant	Effect	Δscore
13:99984944:A:AG	acceptor_gain	1.0000
13:99984944:AG:A	acceptor_gain	1.0000
13:99984945:G:GC	acceptor_loss	1.0000
13:99984945:G:GG	acceptor_gain	1.0000
13:99984945:GG:G	acceptor_gain	1.0000
13:99984945:GGGGA:G	acceptor_gain	1.0000
13:99983137:CAGG:C	donor_loss	0.9900
13:99983140:GTAA:G	donor_loss	0.9900
13:99983141:T:A	donor_loss	0.9900
13:99984942:ACAG:A	acceptor_gain	0.9900
13:99984944:AGG:A	acceptor_gain	0.9900
13:99984945:GGG:G	acceptor_gain	0.9900
13:99985097:G:GT	donor_gain	0.9900
13:99985105:TGAAG:T	donor_loss	0.9900
13:99985106:GAAGG:G	donor_loss	0.9900
13:99985107:A:T	donor_gain	0.9900
13:99985107:AAG:A	donor_loss	0.9900
13:99985108:AGG:A	donor_loss	0.9900
13:99985109:G:GT	donor_loss	0.9900
13:99985110:G:GA	donor_loss	0.9900
13:99985111:T:A	donor_loss	0.9900
13:99984944:AGGG:A	acceptor_gain	0.9700
13:99984945:GGGG:G	acceptor_gain	0.9700
13:99984942:ACAGG:A	acceptor_gain	0.9600
13:99985106:G:GT	donor_gain	0.9600
13:99985319:GCA:G	acceptor_loss	0.9600
13:99985321:AGGTC:A	acceptor_loss	0.9600
13:99985322:G:GA	acceptor_loss	0.9600
13:99983129:G:GT	donor_gain	0.9500
13:99983051:C:T	donor_gain	0.9400

AlphaMissense

3511 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:99982836:T:A	C258S	1.000
13:99982836:T:C	C258R	1.000
13:99982837:G:C	C258S	1.000
13:99982893:T:C	F277L	1.000
13:99982894:T:C	F277S	1.000
13:99982895:C:A	F277L	1.000
13:99982895:C:G	F277L	1.000
13:99982912:T:C	L283P	1.000
13:99982983:T:C	C307R	1.000
13:99983004:T:C	F314L	1.000
13:99983005:T:C	F314S	1.000
13:99983006:C:A	F314L	1.000
13:99983006:C:G	F314L	1.000
13:99983023:T:C	L320P	1.000
13:99983031:C:A	H323N	1.000
13:99983031:C:G	H323D	1.000
13:99983032:A:C	H323P	1.000
13:99983032:A:G	H323R	1.000
13:99983033:C:A	H323Q	1.000
13:99983033:C:G	H323Q	1.000
13:99983037:C:A	R325S	1.000
13:99983043:C:G	H327D	1.000
13:99983045:C:A	H327Q	1.000
13:99983045:C:G	H327Q	1.000
13:99983061:T:C	F333L	1.000
13:99983062:T:C	F333S	1.000
13:99983063:C:A	F333L	1.000
13:99983063:C:G	F333L	1.000
13:99983067:T:A	C335S	1.000
13:99983067:T:C	C335R	1.000

dbSNP variants (sampled 300 via entrez): RS1000071901 (13:99980155 T>A,C), RS1000131147 (13:99986553 A>C,G), RS1000224485 (13:99986900 G>A,T), RS1000392329 (13:99982269 C>T), RS1000605540 (13:99984677 G>A,C), RS1001842755 (13:99986502 G>A,C), RS1002330852 (13:99981335 G>A,C,T), RS1002461651 (13:99987153 C>T), RS1002685130 (13:99981113 T>G), RS1003351541 (13:99981364 C>A,T), RS1003499674 (13:99985573 G>A,C,T), RS1003729768 (13:99980356 C>A,T), RS1003841343 (13:99980409 A>G), RS1003854218 (13:99982671 G>A,C), RS1003892267 (13:99980604 C>A,G)

Disease associations

OMIM: gene MIM:603073 | disease phenotypes: MIM:609637, MIM:236100

GenCC curated gene-disease

Disease	Classification	Inheritance
holoprosencephaly 5	Definitive	Autosomal dominant
holoprosencephaly	Supportive	Autosomal recessive

Mondo (5): holoprosencephaly 5 (MONDO:0012322), congenital nervous system disorder (MONDO:0002320), microcephaly (MONDO:0001149), holoprosencephaly (MONDO:0016296), holoprosencephaly 1 (MONDO:0009349)

Orphanet (1): Holoprosencephaly (Orphanet:2162)

HPO phenotypes

142 total (30 of 142 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000062	Ambiguous genitalia
HP:0000104	Renal agenesis
HP:0000119	Abnormality of the genitourinary system
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000243	Trigonocephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000348	High forehead
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000520	Proptosis
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001858_3	Refractive error	2.000000e-08
GCST002617_3	Hyperopia	7.000000e-06
GCST003997_25	Myopia	9.000000e-25
GCST006291_111	Spherical equivalent or myopia (age of diagnosis)	4.000000e-17
GCST010002_194	Refractive error	2.000000e-76

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C566464	Holoprosencephaly 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression	7
Benzo(a)pyrene	increases expression, increases methylation	5
trichostatin A	affects cotreatment, decreases expression	4
Tetrachlorodibenzodioxin	increases expression	3
Cisplatin	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol A	increases methylation, affects cotreatment	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
tobacco tar	decreases expression	1
nickel sulfate	increases expression	1
resorcinol	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
ICG 001	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Carbamazepine	affects expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Estradiol	increases expression	1
Lead	affects expression	1
Niclosamide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XV98	HEK293 eGFP-ZIC2	Transformed cell line	Female
CVCL_YI81	E006AA ZIC2-/- E5	Cancer cell line	Male
CVCL_YI82	E006AA ZIC2-/- G12	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00005016	Not specified	COMPLETED	Study of the Experiences and Needs of Parents Continuing a Pregnancy Following a Prenatal Diagnosis of Holopresencephaly
NCT00088426	Not specified	COMPLETED	Clinical and Genetic Studies on Holoprosencephaly
NCT00645645	Not specified	COMPLETED	A Study of the Genetic Analysis of Brain Disorders
NCT04691414	Not specified	COMPLETED	Retrospective Study Using Next Generation Sequencing (NGS) on Biological Samples to Improve Genetic Counseling for Patients With Previously Explored Craniofacial Midline Defects.
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.