ZIC3

Chr X

Zic family zinc finger 3

Also known as: HTX, HTX1, VACTERLX, ZNF203

NCBI Gene: 7547 ENSG00000156925 UniProt: O60481

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.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation. Mutations in this gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHeterotaxy, visceral, 1, X-linked

UniProtVACTERL association X-linked with or without hydrocephalus

UniProtCongenital heart defects, multiple types, 1, X-linked

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · congenital heart disease with heterotaxy syndrome · XL · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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 OE?0.00 (0.00–0.36)

0≤0.351.4

Missense OE?0.49 (0.41–0.58)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 0 / 8.3Missense obs/exp: 94 / 192.2Syn Z: 0.92

Background carrier burden — how many people carry a rare variant somewhere in ZIC3?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

311 rare PASS variants

Rare truncating (LoF)

1 in 8,300

20 rare PASS variants

Rare synonymous (reference)

1 in 240

205 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZIC3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 530	1 in 9,400
South Asian	~36k	1 in 430	none seen
Remaining (unassigned)	~31k	1 in 260	none seen
European (Finnish)	~27k	1 in 2,600	≈ 1 in 13,000
Admixed American	~23k	1 in 240	≈ 1 in 10,000
African / African American	~21k	1 in 150	1 in 1,900
East Asian	~20k	1 in 250	1 in 2,400
Ashkenazi Jewish	~13k	1 in 2,100	none seen
Middle Eastern	~2,758	1 in 200	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓