CUX2

Chr 12

cut like homeobox 2

Also known as: CDP2, CUTL2, DEE67, EIEE67

NCBI Gene: 23316ENSG00000111249UniProt: O14529

This gene encodes a protein which contains three CUT domains and a homeodomain; both domains are DNA-binding motifs. A similar gene, whose gene product possesses different DNA-binding activities, is located on chromosome on chromosome 7. Two pseudogenes of this gene have been identified on chromosomes 10 and 4. [provided by RefSeq, Jan 2013]

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 67
475
ClinVar variants
13
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CUX2
⚡
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
13 Pathogenic / Likely Pathogenic· 293 VUS of 475 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.19LOEUF
pLI 1.000
Z-score 6.67
OE 0.09 (0.05–0.19)
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.
3.18Z-score
OE missense 0.70 (0.65–0.75)
615 obs / 880.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

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 (0.05–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.65–0.75)
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.0.90
0≤1.21.6
LoF obs/exp: 6 / 63.2Missense obs/exp: 615 / 880.7Syn Z: 1.62

ClinVar Variant Classifications

475 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic4
VUS293
Likely Benign132
Benign17
Conflicting10
9
Pathogenic
4
Likely Pathogenic
293
VUS
132
Likely Benign
17
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
8
0
9
Likely Pathogenic
1
2
1
0
4
VUS
11
269
12
1
293
Likely Benign
0
63
9
60
132
Benign
0
6
4
7
17
Conflicting
—10
Total123413468465

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

View in ClinVar →

Protein Context — Lollipop Plot

CUX2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CUX2-related developmental epileptic encephalopathy

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.
Pfisterer U et al.·Nat Commun
2020
CUX2/KDM5B/SOX17 Axis Affects the Occurrence and Development of Breast Cancer.
Li L et al.·Endocrinology
2022
CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate.
Suzuki T et al.·Sci Rep
2022
A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder.
Barington M et al.·Eur J Hum Genet
2018
The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.
Chatron N et al.·Ann Neurol
2018
Genomic Variants in NEURL, GJA1 and CUX2 Significantly Increase Genetic Susceptibility to Atrial Fibrillation.
Wang P et al.·Sci Rep
2018
Cell-Free DNA Methylation: The New Frontiers of Pancreatic Cancer Biomarkers' Discovery.
Brancaccio M et al.·Genes (Basel)
2019Review
A Systematic Review of Tissue and Single Cell Transcriptome/Proteome Studies of the Brain in Multiple Sclerosis.
Elkjaer ML et al.·Front Immunol
2022Review
A novel frameshift CUX2 variant in a patient with epilepsy and global developmental delay: Phenotypic and genotypic expansion.
Romano F et al.·Eur J Med Genet
2026Case report
Defective DNA repair: a putative nexus linking immunological diseases, neurodegenerative disorders, and cancer.
Andarawi S et al.·Mutagenesis
2025Review
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