CRBN

protein-coding

cereblon

Gene summary

This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

Previous symbols:

MRT2A

MANE transcript

NM_016302.4

Inheritance

ClinVar variants

P:15U:73B:26

Top phenotype

Intellectual developmental disorder, autosomal recessive 2

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr3:3,144,628-3,179,727

External References & Databases

Ensembl (ENSG00000113851)

Transcript & Mutation Effects

hg38 • Region Span ~35.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual disabilityMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: ClinGen

*CRBN* is located on chromosome 3p26.2 and encodes cereblon, an E3 ubiquitin ligase substrate adapter protein. *CRBN* was first reported in relation to autosomal recessive intellectual disability (ID) in 2004 in a large consanguineous kindred (Higgins et al., PMID: 15557513). Affected individuals presented with non-syndromic mild ID and were found to carry a homozygous nonsense variant. The p.Arg419* variant is in the last exon and escapes nonsense-mediated decay, but results in enhanced autoubiquitination and degradation (PMID: 23983124). Two additional families have been reported. In a consanguineous Syrian family, three individuals with mild ID had a homozygous splice site variant (Reuter et al., 2017, PMID: 28097321). Five affected members of a consanguineous Saudi family with severe ID, seizures, and self-injurious behavior carried a homozygous missense variant (Sheereen et al., 2017, PMID: 28143899); the variant lacked functional evidence of gene impact and was not scored. The mechanism of pathogenicity appears to be biallelic loss of function. This gene-disease relationship is also supported by *Crbn* knock-out mouse models that exhibit deficits in learning and memory, and synaptic defects (PMIDs: 21995942, 29459374). In summary, there is moderate evidence supporting the relationship between *CRBN* and autosomal recessive intellectual disability. Given that only two unrelated families with truncating *CRBN* variants have been identified since the original report in 2004, additional genetic evidence is necessary to strengthen this gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 3, 2021. It was reevaluated on September 4, 2026. As a result of this reevaluation, no additional patients were identified, and the classification did not change. The scoring was updated to be consistent with SOP Version 12.

intellectual developmental disorder, autosomal recessive 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011828

Submitter: G2P

intellectual developmental disorder, autosomal recessive 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011828

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 2AR

Manifestation: 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: 10932263; 15557513; 17036314; 17380424

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRBN variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 58

not providedTotal: 39

not specifiedTotal: 20

Intellectual disability, autosomal recessive 2Total: 14

CRBN-related disorderTotal: 7

Multiple myelomaTotal: 1

Intellectual disabilityTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016302.4. 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				15 clinvar	4 clinvar	19
missense		2 clinvar	68 clinvar	7 clinvar		77
nonsense	2 clinvar	5 clinvar	1 clinvar			8
start loss						0
frameshift	3 clinvar	2 clinvar	3 clinvar			8
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	6	9	73	22	4	114

Highest pathogenic variant AF is 0.00000993937

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016302.4	RefSeq	NP_057386.2	11	MANE Select
ENST00000231948.9	Ensembl	ENSP00000231948.4	11	MANE Select
NM_001173482.1	RefSeq	NP_001166953.1	11	Standard
ENST00000424814.5	Ensembl	ENSP00000411047.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
crbn	Danio rerio	Structure: pectoral fin Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

crbn

Danio rerio

Structure: pectoral fin

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein ubiquitination
negative regulation of protein homooligomerization
negative regulation of ion transmembrane transport
proteasome-mediated ubiquitin-dependent protein catabolic process
positive regulation of protein homodimerization activity

Molecular Function

protein binding
metal ion binding

Cellular Component

nucleus
nucleolus
cytoplasm
membrane
Cul4A-RING E3 ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000231948
Coding exons: 11
Length: 30719
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0404	241	239	1.01	0.0000120	2914
Missense (PolyPhen)		34	50.752	0.66993		616
Synonymous	-1.64	100	81.2	1.23	0.00000409	788
Loss of Function	3.01	11	28.3	0.389	0.00000142	324

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate recognition component of a DCX (DDB1-CUL4-X- box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. May play a role in memory and learning by regulating the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1. Binding of pomalidomide and other thalidomide-related drugs changes the substrate specificity of the human protein, leading to decreased degradation of MEIS2 and other target proteins and increased degradation of MYC, IRF4, IKZF1 and IKZF3. {ECO:0000269|PubMed:18414909, ECO:0000269|PubMed:20223979, ECO:0000269|PubMed:24328678, ECO:0000269|PubMed:25043012, ECO:0000269|PubMed:25108355, ECO:0000305}.;
Disease: DISEASE: Mental retardation, autosomal recessive 2A (MRT2A) [MIM:607417]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs. MRT2A patients display mild mental retardation with a standard IQ ranged from 50 to 70. IQ scores are lower in males than females. Developmental milestones are mildly delayed. There are no dysmorphic or autistic features. {ECO:0000269|PubMed:15557513, ECO:0000269|PubMed:28143899}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.219
RVIS EVS: -0.58
RVIS percentile EVS: 18.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.807

Gene Damage Prediction

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