ZC4H2

Chr XXLRXLD

zinc finger C4H2-type containing

Also known as: HCA127, KIAA1166, MCS, MRXS4, WRWF, WRWFFR, WWS

NCBI Gene: 55906ENSG00000126970UniProt: Q9NQZ6

This gene encodes a member of the zinc finger domain-containing protein family. This family member has a C-terminal zinc finger domain that is characterized by four cysteine residues and two histidine residues, and it also includes a coiled-coil region. This protein has been detected as an autoantigen in hepatocellular carcinoma patients. This gene has been identified as a potential candidate for X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

Wieacker-Wolff syndromeMIM #314580
XLR
Wieacker-Wolff syndrome, female-restrictedMIM #301041
XLD
UniProtWieacker-Wolf syndrome
264
ClinVar variants
102
Pathogenic / LP
0.91
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ZC4H2
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Gene-Disease Validity (ClinGen)
X-linked syndromic intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
102 Pathogenic / Likely Pathogenic· 95 VUS of 264 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.39LOEUF
pLI 0.908
Z-score 2.57
OE 0.00 (0.00–0.39)
Highly constrained

More LoF-intolerant than ~75% 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.
1.51Z-score
OE missense 0.54 (0.43–0.69)
47 obs / 86.6 exp
Tolerant

Mild missense constraint

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 (0.00–0.39)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.54 (0.43–0.69)
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.1.32
0≤1.21.6
LoF obs/exp: 0 / 7.7Missense obs/exp: 47 / 86.6Syn Z: -1.42

ClinVar Variant Classifications

264 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71
Likely Pathogenic31
VUS95
Likely Benign50
Benign12
Conflicting5
71
Pathogenic
31
Likely Pathogenic
95
VUS
50
Likely Benign
12
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
6
53
0
71
Likely Pathogenic
10
11
8
2
31
VUS
2
73
20
0
95
Likely Benign
0
7
17
26
50
Benign
0
3
6
3
12
Conflicting
—5
Total2410010431264

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

View in ClinVar →

Protein Context — Lollipop Plot

ZC4H2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ZC4H2-related arthrogryposis multiplex congenita and intellectual disability

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

ZC4H2-related arthrogryposis multiplex congenita and intellectual disability

definitive
Monoallelic X HemizygousLoss 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

Wieacker-Wolff syndrome

MIM #314580

Molecular basis of disorder known

X-linked recessive

Wieacker-Wolff syndrome, female-restricted

MIM #301041

Molecular basis of disorder known

X-linked dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The pathogenic factor of ZC4H2-associated rare disorder is a postsynaptic regulator for synaptic activity and cognitive function.
Wan LP et al.·Proc Natl Acad Sci U S A
2025
Genotype-Phenotype Correlations and Sex Differences in ZC4H2-Associated Rare Disorder.
Peters S et al.·Pediatr Neurol
2024
Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord.
Wongkittichote P et al.·Clin Genet
2023
Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression.
Li Y et al.·J Mol Cell Biol
2022
Ophthalmic abnormalities in Wieacker-Wolff syndrome.
Comlekoglu T et al.·J AAPOS
2022Case report
Genotype variability in early-onset Hereditary Spastic Paraplegia: a single-center study.
Colona VL et al.·Eur J Paediatr Neurol
2025
Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum.
Pérez-Vidarte F et al.·Ann Clin Transl Neurol
2025
ZC4H2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling.
Ma P et al.·J Mol Cell Biol
2020
Treatment of ZC4H2 Variant-Associated Spastic Paraplegia with Selective Dorsal Rhizotomy and Intensive Postoperative Rehabilitation: A Case Report.
Inotani T et al.·Tohoku J Exp Med
2024Case report
ZC4H2 deletions can cause severe phenotype in female carriers.
Zanzottera C et al.·Am J Med Genet A
2017Case report
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