CUL2

protein-coding

cullin 2, the group of Cullins|MicroRNA protein coding host genes

Gene summary

Enables ubiquitin ligase complex scaffold activity and ubiquitin protein ligase binding activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nucleoplasm. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_003591.4

Inheritance

—

ClinVar variants

P:1U:83B:3

Top phenotype

Moyamoya angiopathy

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr10:35,008,504-35,127,006

External References & Databases

Ensembl (ENSG00000108094)

Transcript & Mutation Effects

hg38 • Region Span ~118.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CUL2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 69

not providedTotal: 7

Moyamoya angiopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003591.4. 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			4 clinvar		2 clinvar	6
missense		1 clinvar	73 clinvar	1 clinvar		75
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	1	83	1	2	87

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 110 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003591.4	RefSeq	NP_003582.2	20	MANE Select
ENST00000374749.8	Ensembl	ENSP00000363881.3	20	MANE Select
NM_001198777.2	RefSeq	NP_001185706.1	20	Standard
NM_001198778.2	RefSeq	NP_001185707.1	21	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cul2	Danio rerio	Structure: intersegmental vessel Quality: aplastic abnormal

Gene / Model

Organism

Observed Phenotype

cul2

Danio rerio

Structure: intersegmental vessel

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Renal cell carcinoma - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)
Ubiquitin mediated proteolysis - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Type 2 papillary renal cell carcinoma

Biological Process

G1/S transition of mitotic cell cycle
ubiquitin-dependent protein catabolic process
cell cycle arrest
negative regulation of cell population proliferation
viral process

Molecular Function

protein binding
ubiquitin protein ligase binding
protein-containing complex binding
ubiquitin protein ligase activity

Cellular Component

nucleoplasm
nucleolus
cytosol
SCF ubiquitin ligase complex
VCB complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000537177
Coding exons: 21
Length: 82092
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125694
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.25	217	400	0.542	0.0000211	5091
Missense (PolyPhen)		42	122.83	0.34194		1704
Synonymous	0.799	123	135	0.912	0.00000747	1283
Loss of Function	6.49	1	51.0	0.0196	0.00000296	608

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000037	0.000035	rare
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 ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. ECS complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). May serve as a rigid scaffold in the complex and may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the ECS complex depends on the substrate recognition component. ECS(VHL) mediates the ubiquitination of hypoxia-inducible factor (HIF). {ECO:0000269|PubMed:10973499, ECO:0000269|PubMed:11384984, ECO:0000269|PubMed:27565346, ECO:0000269|PubMed:9122164}.;

Recessive Scores

pRec: 0.194

Intolerance Scores

RVIS EVS: -0.58
RVIS percentile EVS: 18.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.833

Gene Damage Prediction

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