CUL4B

protein-coding

cullin 4B, the group of Cullins

Gene summary

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]

MANE transcript

NM_001079872.2

Inheritance

ClinVar variants

P:68U:313B:123

Top phenotype

Intellectual developmental disorder, X-linked, syndromic 15 (Cabezas type)

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:120,505,920-120,604,074

External References & Databases

Ensembl (ENSG00000158290)

Transcript & Mutation Effects

hg38 • Region Span ~98.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic, Cabezas typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010306

Submitter: Orphanet

intellectual developmental disorder, X-linked, syndromic, Cabezas typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010306

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic, Cabezas typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010306

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked, syndromic, Cabezas typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010306

Submitter: ClinGen

*CUL4B* was first reported in relation to X-linked intellectual disability, Cabezas type in 2007 (Tarpey et al., PMID: 17236139). CUL4B is a member of the cullin family of proteins that function as scaffold proteins for multiple ubiquitin-protein ligase complexes that regulate the degradation of target proteins. The reported phenotypes in affected males include intellectual disability, hypogonadism, delayed puberty, short stature, relative macrocephaly, central obesity, dysmorphic features, aggressive outbursts, tremor, seizures, and variable cerebral malformations (PMIDs: 17236139, 25385192). Carrier females have skewed X-chromosome inactivation and are unaffected. Six variants (splice, nonsense, frameshift) that have been reported in seven probands in three publications (PMIDs: 17236139, 17273978, 24898194) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by a mouse model (PMID: 22763239). In summary, there is definitive evidence supporting the relationship between *CUL4B* and X-linked intellectual disability, Cabezas type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 21, 2018 (SOP Version 5). As of October 2025, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 11. No new evidence has been added.

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic 15 (Cabezas type)XL

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 8135271; 10978355; 11562927; 17236139; 17273978; 19377476; 20002452; 20014135; 24898194

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CUL4B variants in ClinVar

17 Conditions Cataloged

X-linked intellectual disability Cabezas typeTotal: 220

CUL4B-related disorderTotal: 159

not providedTotal: 158

not specifiedTotal: 51

Inborn genetic diseasesTotal: 47

Intellectual disabilityTotal: 4

CUL4B-related disordersTotal: 2

SeizureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001079872.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	13 clinvar	106 clinvar	4 clinvar	124
missense	2 clinvar	5 clinvar	250 clinvar	10 clinvar	3 clinvar	270
nonsense	11 clinvar	8 clinvar	15 clinvar			34
start loss						0
frameshift	18 clinvar	11 clinvar	1 clinvar			30
splice donor/acceptor (+/-2bp)	6 clinvar	6 clinvar	34 clinvar			46
Total	37	31	313	116	7	504

Highest pathogenic variant AF is 0.000044694032

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001079872.2	RefSeq	NP_001073341.1	20	MANE Select
ENST00000371322.11	Ensembl	ENSP00000360373.5	20	MANE Select
NM_001330624.2	RefSeq	NP_001317553.1	21	Standard
NM_001369145.1	RefSeq	NP_001356074.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide excision repair - Homo sapiens (human)
Ubiquitin mediated proteolysis - Homo sapiens (human)
miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

G1/S transition of mitotic cell cycle
nucleotide-excision repair, DNA damage recognition
transcription-coupled nucleotide-excision repair
nucleotide-excision repair, preincision complex stabilization
nucleotide-excision repair, preincision complex assembly

Molecular Function

damaged DNA binding
protein binding
ubiquitin protein ligase binding
ubiquitin protein ligase activity

Cellular Component

nucleoplasm
cytosol
SCF ubiquitin ligase complex
cullin-RING ubiquitin ligase complex
Cul4B-RING E3 ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000404115
Coding exons: 21
Length: 51186
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125730
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.77	126	314	0.401	0.0000218	6077
Missense (PolyPhen)		10	77.472	0.12908		1547
Synonymous	-0.522	119	112	1.06	0.00000790	1628
Loss of Function	5.48	0	35.0	0.00	0.00000254	642

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00018	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition subunit. CUL4B may act within the complex as a scaffold protein, contributing to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. Plays a role as part of the E3 ubiquitin-protein ligase complex in polyubiquitination of CDT1, histone H2A, histone H3 and histone H4 in response to radiation- induced DNA damage. Targeted to UV damaged chromatin by DDB2 and may be important for DNA repair and DNA replication. Required for ubiquitination of cyclin E, and consequently, normal G1 cell cycle progression. Regulates the mammalian target-of-rapamycin (mTOR) pathway involved in control of cell growth, size and metabolism. Specific CUL4B regulation of the mTORC1-mediated pathway is dependent upon 26S proteasome function and requires interaction between CUL4B and MLST8. {ECO:0000269|PubMed:14578910, ECO:0000269|PubMed:16322693, ECO:0000269|PubMed:16678110, ECO:0000269|PubMed:18235224, ECO:0000269|PubMed:18593899, ECO:0000269|PubMed:19801544, ECO:0000269|PubMed:22118460}.;
Disease: DISEASE: Mental retardation, X-linked, syndromic, 15 (MRXS15) [MIM:300354]: A syndromic form of X-linked mental retardation characterized by severe intellectual deficit associated with short stature, craniofacial dysmorphism, small testes, muscle wasting in lower legs, kyphosis, joint hyperextensibility, pes cavus, small feet, and abnormalities of the toes. Additional neurologic manifestations include speech delay and impairment, tremor, seizures, gait ataxia, hyperactivity and decreased attention span. {ECO:0000269|PubMed:17236139, ECO:0000269|PubMed:17273978, ECO:0000269|PubMed:19377476, ECO:0000269|PubMed:20002452}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

RVIS EVS: -0.36
RVIS percentile EVS: 28.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.559

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium