ZIC1

Chr 3AD

Zic family zinc finger 1

Also known as: BAIDCS, CRS6, ZIC, ZNF201

NCBI Gene: 7545 ENSG00000152977 UniProt: Q15915 OMIM: 600470

This gene encodes a zinc finger transcription factor that acts as a transcriptional activator involved in neurogenesis and plays important roles in early CNS organogenesis, dorsal spinal cord development, and cerebellar maturation. Mutations cause craniosynostosis 6 and structural brain anomalies with impaired intellectual development and craniosynostosis, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants, indicating that proper protein function is critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.362 OMIM phenotypes

Clinical Summary— ZIC1

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Gene-Disease Validity (ClinGen)

craniosynostosis 6 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 96 VUS of 205 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.08 (0.03–0.36)

0≤0.351.4

Missense OE?0.57 (0.50–0.65)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 1 / 13.0Missense obs/exp: 160 / 281.3Syn Z: -2.81

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveZIC1-related craniosynostosisGOFAD

This gene — mechanism propensity

0.5870th %ile

GOF

0.2597th %ile

LOF

0.88top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 54% of P/LP variants are LoF · LOEUF 0.36

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFHeterozygous gain of function mutations in the ZIC1 gene have been described with syndromic craniosynostosis, variable cerebral or cerebellar abnormalities and mild to moderate developmental delay.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 30391508 ↗

ClinVar Variant Classifications

205 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic7

VUS96

Likely Benign77

Benign15

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	2	0	0	6
Likely Pathogenic	3	4	0	0	7
VUS	4	88	3	1	96
Likely Benign	0	8	12	57	77
Benign	0	5	4	6	15
Conflicting	—				2
Total	11	107	19	64	203

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ZIC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →