ZIC2

Chr 13AD

Zic family zinc finger 2

Also known as: HPE5

NCBI Gene: 7546ENSG00000043355UniProt: O95409OMIM: 603073

ZIC2 encodes a zinc finger transcription factor that acts as both an activator and repressor, playing critical roles in early central nervous system development and retinal projection formation. Mutations cause holoprosencephaly type 5, the most common structural brain malformation, which is inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants, reflecting its essential role in normal brain development.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.271 OMIM phenotype
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
64 unique Pathogenic / Likely Pathogenic· 68 VUS of 200 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — ZIC2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
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
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
LoF OE0.00 (0.00–0.27)
0≤0.351.4
Missense OE0.41 (0.35–0.49)
0≤0.61.4
Synonymous OE1.37
0≤1.21.6
LoF obs/exp: 0 / 11.2Missense obs/exp: 98 / 237.2Syn Z: -2.95
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveZIC2-related holoprosencephalyLOFAD
DN
0.4884th %ile
GOF
0.2596th %ile
LOF
0.91top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 25% of P/LP variants are LoF · LOEUF 0.27

Literature Evidence

LOFHaploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.PMID:9771712

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

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53
Likely Pathogenic11
VUS68
Likely Benign57
Benign9
Conflicting2
53
Pathogenic
11
Likely Pathogenic
68
VUS
57
Likely Benign
9
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
2
38
0
53
Likely Pathogenic
3
5
3
0
11
VUS
0
60
8
0
68
Likely Benign
0
0
6
51
57
Benign
0
0
3
6
9
Conflicting
—2
Total16675857200

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients