CUX2

Chr 12

cut like homeobox 2

Also known as: CDP2, CUTL2, DEE67, EIEE67

NCBI Gene: 23316 ENSG00000111249 UniProt: O14529

This gene encodes a transcription factor that regulates neuronal proliferation, differentiation, dendrite development, and synaptogenesis in cortical layers II-III through sequence-specific DNA binding. Mutations cause developmental and epileptic encephalopathy 67 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to cause severe developmental consequences.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.19

Clinical Summary— CUX2

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ADModerate

Moderate evidence — consider for supplementary testing

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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.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 299 VUS of 478 total submissions

Explore recent and relevant literature in Research Assistant →

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?

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?

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?

LoF OE?0.09 (0.05–0.19)

0≤0.351.4

Missense OE?0.70 (0.65–0.75)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 6 / 63.2Missense obs/exp: 615 / 880.7Syn Z: 1.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCUX2-related developmental epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.3395th %ile

GOF

0.3590th %ile

LOF

0.76top 10%

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

LOFprediction above median · LOEUF 0.19

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

478 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic3

VUS299

Likely Benign138

Benign16

Conflicting11

Pathogenic

Likely Pathogenic

299

VUS

138

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	1	2	0	0	3
VUS	14	274	10	1	299
Likely Benign	0	65	9	64	138
Benign	0	7	3	6	16
Conflicting	—				11
Total	15	349	22	71	468

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap CUX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →