ZC4H2

Chr XXLRXLD

zinc finger C4H2-type containing

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

NCBI Gene: 55906 ENSG00000126970 UniProt: Q9NQZ6 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

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

59 unique Pathogenic / Likely Pathogenic· 84 VUS of 245 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 OE?0.00 (0.00–0.39)

0≤0.351.4

Missense OE?0.54 (0.43–0.69)

0≤0.61.4

Synonymous OE?1.32

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

This gene — mechanism propensity

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 · 56% of P/LP variants are LoF · LOEUF 0.39 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

245 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic32

VUS84

Likely Benign49

Benign12

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	5	4	0	27
Likely Pathogenic	15	13	2	2	32
VUS	4	75	5	0	84
Likely Benign	0	7	16	26	49
Benign	0	3	6	3	12
Conflicting	—				5
Total	37	103	33	31	209

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap ZC4H2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →