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…

Primary Disease Associations & Inheritance

Wieacker-Wolff syndromeMIM #314580

XLR

Wieacker-Wolff syndrome, female-restrictedMIM #301041

XLD

UniProtWieacker-Wolf syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · X-linked syndromic intellectual disability · XL · ClinGen 2020

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

0.39

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

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

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

Background carrier burden — how many people carry a rare variant somewhere in ZC4H2?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 320

174 rare PASS variants

Rare truncating (LoF)

1 in 8,600

4 rare PASS variants

Rare synonymous (reference)

1 in 710

83 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZC4H2. 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 300	1 in 7,600
South Asian	~36k	1 in 210	none seen
Remaining (unassigned)	~31k	1 in 360	1 in 3,100
European (Finnish)	~27k	1 in 730	none seen
Admixed American	~23k	1 in 350	≈ 1 in 23,000
African / African American	~21k	1 in 460	none seen
East Asian	~20k	1 in 410	none seen
Ashkenazi Jewish	~13k	1 in 990	none seen
Middle Eastern	~2,758	≈ 1 in 2,700	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 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓