ZIC3

Chr XXLR

Zic family zinc finger 3

Also known as: HTX, HTX1, VACTERLX, ZNF203

NCBI Gene: 7547ENSG00000156925UniProt: O60481OMIM: 300265

The protein functions as a transcriptional activator that binds to GLI-consensus sequences and is required for axial midline development and left-right asymmetry specification during early embryogenesis. Loss-of-function mutations cause X-linked visceral heterotaxy with congenital heart defects and left-right axis defects in organs, as well as VACTERL association. The condition follows X-linked recessive inheritance.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismXLRLOEUF 0.363 OMIM phenotypes
Clinical Summary— ZIC3
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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.
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 0.925
Z-score 2.67
OE 0.00 (0.00–0.36)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.52Z-score
OE missense 0.49 (0.41–0.58)
94 obs / 192.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.36)
0≤0.351.4
Missense OE0.49 (0.41–0.58)
0≤0.61.4
Synonymous OE0.87
0≤1.21.6
LoF obs/exp: 0 / 8.3Missense obs/exp: 94 / 192.2Syn Z: 0.92
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveZIC3-related heterotaxy syndromeLOFXLR
definitiveZIC3-related VACTERL association with or without hydrocephalusOTHERXLR
DN
0.4884th %ile
GOF
0.2198th %ile
LOF
0.90top 5%

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

LOFprediction above median · LOEUF 0.36

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

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

ZIC3 · 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.

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Clinical Literature
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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
Zic3 represses anterior digit development in tetrapods.
Li SS et al.·Zool Res
2025Open Access
Zic3 enables bimodal regulation of tyrosine hydroxylase expression in olfactory bulb and midbrain-derived neurons.
Bhaskar S et al.·Cell Death Discov
2025Open Access
A CRISPR mis-insertion in the Zic3 5'UTR inhibits in vivo translation and is predicted to result in formation of an mRNA stem-loop hairpin.
Bellchambers HM et al.·Biol Open
2025Open Access
ZIC3 shapes digit morphogenesis in avian: Research Note: Zic3 shapes anterior digit morphogenesis in avian diversity.
Li S et al.·Poult Sci
2025Open Access
ApoM maintains cellular homeostasis between mitophagy and apoptosis by affecting the stability of Nnt mRNA through the Zic3-ApoM-Elavl2-Nnt axis during neural tube closure.
Liu Q et al.·Cell Death Dis
2025Open Access
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