CUX2

Chr 12AD

cut like homeobox 2

Also known as: CDP2, CUTL2, DEE67, EIEE67

NCBI Gene: 23316 ENSG00000111249 UniProt: O14529 OMIM: 610648

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 67MIM #618141

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · genetic developmental and epileptic encephalopathy · AD · ClinGen 2023

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

LOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in CUX2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 36

1,799 rare PASS variants

Rare truncating (LoF)

1 in 500

123 rare PASS variants

Rare synonymous (reference)

1 in 46

916 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CUX2. 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)	~556k	1 in 40	1 in 690
South Asian	~43k	1 in 29	1 in 1,200
Remaining (unassigned)	~30k	1 in 33	1 in 430
European (Finnish)	~27k	1 in 87	1 in 920
Admixed American	~22k	1 in 35	1 in 1,300
African / African American	~21k	1 in 35	1 in 310
East Asian	~20k	1 in 41	1 in 490
Ashkenazi Jewish	~13k	1 in 150	1 in 610
Middle Eastern	~2,884	1 in 27	≈ 1 in 1,400

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): 20 of 22 coding exons well covered in gnomAD exomes; exons 1, 2 marginal. Genomes: 21 of 22 (exon 1 below).? see exons ↓