ZIC1

Chr 3AD

Zic family zinc finger 1

Also known as: BAIDCS, CRS6, ZIC, ZNF201

NCBI Gene: 7545ENSG00000152977UniProt: Q15915

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Craniosynostosis 6MIM #616602
AD
Structural brain anomalies with impaired intellectual development and craniosynostosisMIM #618736
AD
223
ClinVar variants
31
Pathogenic / LP
0.93
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ZIC1
🧬
Gene-Disease Validity (ClinGen)
craniosynostosis 6 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 97 VUS of 223 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.36LOEUF
pLI 0.934
Z-score 3.09
OE 0.08 (0.03–0.36)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.57Z-score
OE missense 0.57 (0.50–0.65)
160 obs / 281.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.03–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.50–0.65)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.32
0≤1.21.6
LoF obs/exp: 1 / 13.0Missense obs/exp: 160 / 281.3Syn Z: -2.81

ClinVar Variant Classifications

223 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic9
VUS97
Likely Benign78
Benign15
Conflicting2
22
Pathogenic
9
Likely Pathogenic
97
VUS
78
Likely Benign
15
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
20
0
22
Likely Pathogenic
0
4
5
0
9
VUS
3
85
8
1
97
Likely Benign
0
8
13
57
78
Benign
0
5
4
6
15
Conflicting
—2
Total41035064223

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ZIC1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ZIC1-related craniosynostosis

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Craniosynostosis 6

MIM #616602

Molecular basis of disorder known

Autosomal dominant

Structural brain anomalies with impaired intellectual development and craniosynostosis

MIM #618736

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ZIC1 Function in Normal Cerebellar Development and Human Developmental Pathology.
Aruga J et al.·Adv Exp Med Biol
2018Review
Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling.
Kutkowska-Kaźmierczak A et al.·J Appl Genet
2018Review
Role of ZIC1 methylation in hepatocellular carcinoma and its clinical significance.
Wang YY et al.·Tumour Biol
2014
Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.
Hopfner F et al.·Mov Disord
2022
Clinical and molecular approaches to well differentiated and dedifferentiated liposarcoma.
Crago AM et al.·Curr Opin Oncol
2011Review
Caput membranaceum: A novel clinical presentation of ZIC1 related skull malformation and craniosynostosis.
Sasaki E et al.·Am J Med Genet A
2020Case report
Molecular Biology of Pediatric Hydrocephalus and Hydrocephalus-related Diseases.
Yamasaki M et al.·Neurol Med Chir (Tokyo)
2015Review
Single-cell transcriptome reveals Staphylococcus aureus modulating fibroblast differentiation in the bone-implant interface.
Yu J et al.·Mol Med
2023Meta-analysis
Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing.
Yoon JG et al.·BMC Med Genomics
2025
Roles of ZIC family genes in human gastric cancer.
Ma G et al.·Int J Mol Med
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
CircRNA_02540 alleviated the migration and ligament differentiation capacities of SM-MSCs suppressed by chronic inflammation via regulating miR-203a-3p/ZIC1 pathway.
Liu Y et al.·J Mol Histol
2026
Unilateral craniosynostosis associated with ZIC1 gene mutation: a case report.
Alsharef FK et al.·J Surg Case Rep
2026🔓 Open AccessCase report
ZIC1 transcription factor overexpression in segmental bone defects is associated with brown adipogenic and osteogenic differentiation.
Thottappillil N et al.·Stem Cells
2025
Dorsoventral patterning beyond the gastrulation stage: Interpretation of early dorsoventral cues and modular development mediated by zic1/zic4.
Kawanishi T et al.·Cells Dev
2025
ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.
Lee JJY et al.·Nat Genet
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools