ZIC2

Chr 13AD

Zic family zinc finger 2

Also known as: HPE5

NCBI Gene: 7546ENSG00000043355UniProt: O95409

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. [provided by RefSeq, Jul 2016]

Primary Disease Associations & Inheritance

Holoprosencephaly 5MIM #609637
AD
597
ClinVar variants
121
Pathogenic / LP
0.97
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ZIC2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
121 Pathogenic / Likely Pathogenic· 274 VUS of 597 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.27LOEUF
pLI 0.974
Z-score 3.10
OE 0.00 (0.00–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.21Z-score
OE missense 0.41 (0.35–0.49)
98 obs / 237.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.00 (0.00–0.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.41 (0.35–0.49)
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.1.37
0≤1.21.6
LoF obs/exp: 0 / 11.2Missense obs/exp: 98 / 237.2Syn Z: -2.95

ClinVar Variant Classifications

597 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic99
Likely Pathogenic22
VUS274
Likely Benign175
Benign17
Conflicting10
99
Pathogenic
22
Likely Pathogenic
274
VUS
175
Likely Benign
17
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
2
82
0
99
Likely Pathogenic
8
7
7
0
22
VUS
1
206
65
2
274
Likely Benign
1
3
21
150
175
Benign
0
0
10
7
17
Conflicting
—10
Total25218185159597

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

View in ClinVar →

Protein Context — Lollipop Plot

ZIC2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ZIC2-related holoprosencephaly

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Holoprosencephaly 5

MIM #609637

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ZIC2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
FOXM1-regulated ZIC2 promotes the malignant phenotype of renal clear cell carcinoma by activating UBE2C/mTOR signaling pathway.
Lv Z et al.·Int J Biol Sci
2023
Holoprosencephaly.
Dubourg C et al.·Orphanet J Rare Dis
2007Review
ZIC2 in Holoprosencephaly.
Barratt KS et al.·Adv Exp Med Biol
2018Review
Cohesin complex-associated holoprosencephaly.
Kruszka P et al.·Brain
2019
Rare nasal cleft in a patient with holoprosencephaly due to a mutation in the ZIC2 gene.
Savastano CP et al.·Birth Defects Res A Clin Mol Teratol
2014Review
ZIC2 induces pro-tumor macrophage polarization in nasopharyngeal carcinoma by activating the JUNB/MCSF axis.
Liu Q et al.·Cell Death Dis
2023
ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer.
Liu ZH et al.·Int J Cancer
2020
Zic2 mutation causes holoprosencephaly via disruption of NODAL signalling.
Houtmeyers R et al.·Hum Mol Genet
2016
Zic2 hypomorphic mutant mice as a schizophrenia model and ZIC2 mutations identified in schizophrenia patients.
Hatayama M et al.·Sci Rep
2011Cohort
IGF2BP1-mediated N6-methyladenosine modification promotes intrahepatic cholangiocarcinoma progression.
Xiao P et al.·Cancer Lett
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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