CUL4B

Chr XXLR

cullin 4B

Also known as: CUL-4B, MRXHF2, MRXS15, MRXSC, SFM2

NCBI Gene: 8450ENSG00000158290UniProt: Q13620

This gene is a member of the cullin family. The encoded protein forms a complex that functions as an E3 ubiquitin ligase and catalyzes the polyubiquitination of specific protein substrates in the cell. The protein interacts with a ring finger protein, and is required for the proteolysis of several regulators of DNA replication including chromatin licensing and DNA replication factor 1 and cyclin E. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Cabezas typeMIM #300354
XLR
350
ClinVar variants
79
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— CUL4B
🧬
Gene-Disease Validity (ClinGen)
X-linked intellectual disability, Cabezas type · XLDefinitive

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
79 Pathogenic / Likely Pathogenic· 128 VUS of 350 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.09LOEUF
pLI 1.000
Z-score 5.48
OE 0.00 (0.00–0.09)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
3.77Z-score
OE missense 0.40 (0.35–0.47)
126 obs / 314.1 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.0.00 (0.00–0.09)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.40 (0.35–0.47)
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.1.06
0≤1.21.6
LoF obs/exp: 0 / 35.0Missense obs/exp: 126 / 314.1Syn Z: -0.52

ClinVar Variant Classifications

350 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic17
VUS128
Likely Benign106
Benign32
Conflicting5
62
Pathogenic
17
Likely Pathogenic
128
VUS
106
Likely Benign
32
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
1
48
0
62
Likely Pathogenic
8
1
7
1
17
VUS
2
99
25
2
128
Likely Benign
0
5
49
52
106
Benign
0
2
23
7
32
Conflicting
—5
Total2310815262350

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

View in ClinVar →

Protein Context — Lollipop Plot

CUL4B · protein map & ClinVar variants

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

Gene2Phenotype Curations

CUL4B-related syndromic intellectual developmental disorder, Cabezas type

definitive
Monoallelic X HemizygousLoss 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
CULLIN 4B; CUL4B
MIM #300304 · *

Intellectual developmental disorder, X-linked syndromic, Cabezas type

MIM #300354

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.
Grozeva D et al.·Hum Mutat
2015
MEN1 Degradation Induced by Neddylation and the CUL4B-DCAF7 Axis Promotes Pancreatic Neuroendocrine Tumor Progression.
Xu J et al.·Cancer Res
2023
CUL4B-associated epilepsy: Report of a novel truncating variant promoting drug-resistant seizures and systematic review of the literature.
Della Vecchia S et al.·Seizure
2023Case report
CUL4B-deficiency in humans: understanding the clinical consequences of impaired Cullin 4-RING E3 ubiquitin ligase function.
Kerzendorfer C et al.·Mech Ageing Dev
2011Review
PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling.
Ma N et al.·Nat Commun
2021
Genome-first approach for the characterization of a complex phenotype with combined NBAS and CUL4B deficiency.
Ritelli M et al.·Bone
2020Review
CUL4B enhances the malignant phenotype of esophageal squamous cell carcinoma by suppressing TGFBR3 expression.
Gong Q et al.·Biochem Biophys Res Commun
2023
A novel CUL4B gene variant activating Wnt4/β-catenin signal pathway to karyotype 46, XY female with disorders of sex development.
Wang C et al.·Biol Res
2025
A new CUL4B variant associated with a mild phenotype and an exceptional pattern of leukoencephalopathy.
Weissbach S et al.·Am J Med Genet A
2017Case report
CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma.
Li Y et al.·Cell Cycle
2019
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
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools