ZC4H2

Chr XXLRXLD

zinc finger C4H2-type containing

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

NCBI Gene: 55906ENSG00000126970UniProt: Q9NQZ6OMIM: 300897

This gene encodes a zinc finger protein that regulates interneuron differentiation and neuromuscular junction formation during neuronal development. Mutations cause Wieacker-Wolff syndrome, characterized by intellectual disability and neuromuscular abnormalities, with X-linked inheritance that can affect both males and females. The gene is highly constrained against loss-of-function variants (pLI 0.91, LOEUF 0.39), indicating that functional copies are essential for normal development.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismXLR/XLDLOEUF 0.392 OMIM phenotypes
Clinical Summary— ZC4H2
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Gene-Disease Validity (ClinGen)
X-linked syndromic intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.
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ClinVar Variants
99 unique Pathogenic / Likely Pathogenic· 98 VUS of 300 total submissions
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
0.39LOEUF
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
1.51Z-score
OE missense 0.54 (0.43–0.69)
47 obs / 86.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.00 (0.00–0.39)
0≤0.351.4
Missense OE0.54 (0.43–0.69)
0≤0.61.4
Synonymous OE1.32
0≤1.21.6
LoF obs/exp: 0 / 7.7Missense obs/exp: 47 / 86.6Syn Z: -1.42
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveZC4H2-related arthrogryposis multiplex congenita and intellectual disabilityLOFmonoallelic_X_heterozygous
definitiveZC4H2-related arthrogryposis multiplex congenita and intellectual disabilityLOFXLR
DN
0.3793th %ile
GOF
0.4777th %ile
LOF
0.71top 10%

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

LOFprediction above median · 33% of P/LP variants are LoF · LOEUF 0.39

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

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65
Likely Pathogenic34
VUS98
Likely Benign50
Benign12
Conflicting5
65
Pathogenic
34
Likely Pathogenic
98
VUS
50
Likely Benign
12
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
6
41
0
65
Likely Pathogenic
15
13
4
2
34
VUS
4
76
18
0
98
Likely Benign
0
7
17
26
50
Benign
0
3
6
3
12
Conflicting
—5
Total371058631264

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.

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 4 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