CHD4

Chr 12AD

chromodomain helicase DNA binding protein 4

Also known as: CHD-4, Mi-2b, Mi2-BETA, SIHIWES

NCBI Gene: 1108ENSG00000111642UniProt: Q14839

The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein. Somatic mutations in this gene are associated with serous endometrial tumors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

Primary Disease Associations & Inheritance

Sifrim-Hitz-Weiss syndromeMIM #617159
AD
533
ClinVar variants
61
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CHD4
🧬
Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 269 VUS of 533 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.16LOEUF
pLI 1.000
Z-score 8.76
OE 0.09 (0.06–0.16)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
6.34Z-score
OE missense 0.46 (0.43–0.50)
504 obs / 1094.3 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.09 (0.06–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.43–0.50)
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.1.03
0≤1.21.6
LoF obs/exp: 10 / 108.4Missense obs/exp: 504 / 1094.3Syn Z: -0.52

ClinVar Variant Classifications

533 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic44
VUS269
Likely Benign154
Benign34
Conflicting15
17
Pathogenic
44
Likely Pathogenic
269
VUS
154
Likely Benign
34
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
5
12
0
17
Likely Pathogenic
7
34
3
0
44
VUS
7
221
36
5
269
Likely Benign
1
17
65
71
154
Benign
0
4
12
18
34
Conflicting
—15
Total1528112894533

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

View in ClinVar →

Protein Context — Lollipop Plot

CHD4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CHD4-related syndromic intellectual disability with or without congenital heart disease

definitive
ADLoss 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

Sifrim-Hitz-Weiss syndrome

MIM #617159

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CHD4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.
Weiss K et al.·Genet Med
2020
Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome.
Karimi K et al.·Am J Hum Genet
2025
The NuRD complex and macrocephaly associated neurodevelopmental disorders.
Pierson TM et al.·Am J Med Genet C Semin Med Genet
2019Review
In silico Analysis of CHD4 Mutations Reveals Domain-Specific Impacts on Cardiovascular Disorders Among Patients With Rare Diseases.
Novillo A et al.·Hum Mutat
2026Review
CHD4 Promotes Breast Cancer Progression as a Coactivator of Hypoxia-Inducible Factors.
Wang Y et al.·Cancer Res
2020
Gene mutations in comorbidity of epilepsy and arrhythmia.
Yu C et al.·J Neurol
2023Review
CHD4 variants are associated with childhood idiopathic epilepsy with sinus arrhythmia.
Liu XR et al.·CNS Neurosci Ther
2021
Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4 degradation and Wnt/β-catenin pathway inhibition.
Xiao G et al.·J Transl Med
2024
Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations.
Song B et al.·Cancer Res Treat
2024
CHD4 as an important mediator in regulating the malignant behaviors of colorectal cancer.
Chang CL et al.·Int J Biol Sci
2021
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