CUL7

Summary

CUL7 (cullin 7, HGNC:21024) is a protein-coding gene on chromosome 6p21.1, encoding Cullin-7 (Q14999). Core component of the 3M and Cul7-RING(FBXW8) complexes, which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.

The protein encoded by this gene is a component of an E3 ubiquitin-protein ligase complex. The encoded protein interacts with TP53, CUL9, and FBXW8 proteins. Defects in this gene are a cause of 3M syndrome type 1 (3M1). Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9820 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3M syndrome 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,044 total — 72 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 72
• MANE Select transcript: NM_014780

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21024
Approved symbol	CUL7
Name	cullin 7
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	dJ20C7.5
Ensembl gene	ENSG00000044090
Ensembl biotype	protein_coding
OMIM	609577
Entrez	9820

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 14 protein_coding, 9 retained_intron, 4 nonsense_mediated_decay

ENST00000265348, ENST00000478630, ENST00000673725, ENST00000673753, ENST00000674100, ENST00000674112, ENST00000674134, ENST00000683160, ENST00000683242, ENST00000683320, ENST00000683493, ENST00000685042, ENST00000686442, ENST00000687225, ENST00000688302, ENST00000688707, ENST00000689256, ENST00000690231, ENST00000692002, ENST00000857866, ENST00000857867, ENST00000930001, ENST00000930002, ENST00000952316, ENST00000952317, ENST00000952318, ENST00000952319

RefSeq mRNA: 5 — MANE Select: NM_014780 NM_001168370, NM_001374872, NM_001374873, NM_001374874, NM_014780

CCDS: CCDS4881, CCDS55003

Canonical transcript exons

ENST00000265348 — 26 exons

Exon	Start	End
ENSE00000518395	43050968	43051468
ENSE00000518397	43049963	43050159
ENSE00000518399	43048332	43048569
ENSE00000518410	43043074	43043180
ENSE00000518411	43042802	43042984
ENSE00000518412	43040915	43041075
ENSE00000518415	43038842	43038987
ENSE00000751543	43038566	43038692
ENSE00000751547	43040156	43040426
ENSE00000751549	43040530	43040746
ENSE00000751557	43043448	43043630
ENSE00000751563	43045227	43045402
ENSE00000751715	43049407	43049662
ENSE00000751717	43050260	43050398
ENSE00000751724	43051612	43051763
ENSE00000850041	43037617	43038011
ENSE00000850042	43038267	43038472
ENSE00000850047	43048148	43048253
ENSE00000850048	43052209	43052796
ENSE00002458791	43044752	43044885
ENSE00003535865	43046880	43047107
ENSE00003582012	43045587	43045682
ENSE00003587349	43046236	43046407
ENSE00003591202	43045986	43046091
ENSE00003604965	43046511	43046601
ENSE00003902364	43053622	43053851

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 93.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.4976 / max 74.0075, expressed in 1791 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73661	4.9463	1596
73662	4.3489	1648
73663	3.1041	1481
73660	1.0983	735

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	93.13	gold quality
pituitary gland	UBERON:0000007	91.70	gold quality
adenohypophysis	UBERON:0002196	90.91	gold quality
right uterine tube	UBERON:0001302	89.60	gold quality
endometrium epithelium	UBERON:0004811	88.37	gold quality
adrenal tissue	UBERON:0018303	87.56	gold quality
right adrenal gland	UBERON:0001233	87.44	gold quality
right adrenal gland cortex	UBERON:0035827	87.03	gold quality
right lobe of thyroid gland	UBERON:0001119	86.78	gold quality
ventricular zone	UBERON:0003053	86.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.69	gold quality
endocervix	UBERON:0000458	86.39	gold quality
left ovary	UBERON:0002119	86.31	gold quality
cerebellar hemisphere	UBERON:0002245	86.05	gold quality
right ovary	UBERON:0002118	85.95	gold quality
cerebellar cortex	UBERON:0002129	85.95	gold quality
left adrenal gland	UBERON:0001234	85.93	gold quality
left lobe of thyroid gland	UBERON:0001120	85.85	gold quality
body of uterus	UBERON:0009853	85.73	gold quality
left adrenal gland cortex	UBERON:0035825	85.69	gold quality
adrenal cortex	UBERON:0001235	85.65	gold quality
cerebellum	UBERON:0002037	85.31	gold quality
thyroid gland	UBERON:0002046	85.25	gold quality
adrenal gland	UBERON:0002369	85.24	gold quality
ganglionic eminence	UBERON:0004023	85.12	gold quality
body of pancreas	UBERON:0001150	85.09	gold quality
metanephros cortex	UBERON:0010533	84.94	gold quality
cortical plate	UBERON:0005343	84.92	gold quality
paraflocculus	UBERON:0005351	84.85	silver quality
apex of heart	UBERON:0002098	84.59	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.22

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• 25 distinct mutations in the gene cullin 7 mappped to chromosome 6 were identified in 29 families with 3-M syndrome. (PMID:16142236)
• CUL7 functions to promote cell growth through, in part, antagonizing the function of p53 (PMID:16547496)
• p53-binding domain of CUL7 contributes to the cytoplasmic localization of CUL7 (PMID:16875676)
• CPH domain interaction surface of p53 resides in the tetramerization domain and is formed by residues contributed by at least two subunits (PMID:17298945)
• PARC and CUL7 subcomplexes exhibit E3 ubiquitin ligase activity in vitro. (PMID:17332328)
• In a proteomic screen for p53 interactors the cullin protein Cul7 efficiently associates with p53. (PMID:17586686)
• A novel homozygous 4582insT mutation in CUL7 resulted in a frameshift mutation & a premature stop codon at 1553 (Q1553X)in Yakuts with short stature syndromes. (PMID:17675530)
• CUL7 is a new oncogene that cooperates with Myc in transformation by blocking Myc-induced apoptosis in a p53-dependent manner. (PMID:17942889)
• in 33 novel cases of 3M syndrome, we identified deleterious CUL7 mutations in 23/33 patients, including 19 novel mutations & 1 paternal isodisomy of chromosome 6 encompassing a CUL7 mutation; findings also support genetic heterogeneity of this disease (PMID:19225462)
• CUL7 expression in placenta is up-regulated up to 10 times in intra-uterine growth restriction (IUGR) and up to 15 times in preeclampsia associated with IUGR; the CUL7 promoter is hypomethylated in IUGR. (PMID:20005570)
• CUL7 appears to be the major gene responsible for 3M syndrome accounting for 77.5% of cases while OBSL1 mutations accounts for 16.3%[review] (PMID:21396581)
• We propose that CUL7, OBSL1, and CCDC8 are members of a pathway controlling mammalian growth. (PMID:21737058)
• binding of Cul1-Rbx1 to Cul7-Rbx1 is mediated via heterodimerization of Fbxw8 with other F-box proteins which function to recruit substrates into the E3 ligase complex (PMID:21946088)
• discussion of roles of CUL7, OBSL1 (obscurin-like 1), and CCDC8 (coiled-coil domain containing protein 8) in growth and development using findings from patients with Miller-McKusick-Malvaux syndrome and Silver-Russell syndrome [REVIEW] (PMID:22156540)
• Dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in intrauterine growth restriction. (PMID:22524683)
• This study demonstrates specific genomic alterations in HCC/MS and points to CUL7 as a novel gene potentially involved in liver carcinogenesis associated with metabolic Syndrome, the amplification of which might influence cell proliferation. (PMID:22942238)
• Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. (PMID:23018678)
• Growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8. (PMID:23029530)
• Homozygous deletion in exon 18 of the CUL7 gene, which has not been previously described, could be responsible for the 3-M syndrome. (PMID:23517720)
• CUL7/Fbxw8 ubiquitin ligase-mediated HPK1 degradation revealed a direct link and novel role of CUL7/Fbxw8 ubiquitin ligase in the MAPK pathway, which plays a critical role in cell proliferation and differentiation. (PMID:24362026)
• CUL7, OBSL1 and CCDC8 modulate the alternative splicing of the INSR (PMID:24711643)
• The CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development. (PMID:24793695)
• study provided evidence that Cullin7 functions as a novel oncogene in breast cancer and may be a potential therapeutic target for breast cancer management (PMID:25003318)
• our study provided evidence that Cullin7 functions as a novel oncogene in lung cancer and may be a potential therapeutic target for lung cancer management. (PMID:25706399)
• report an adult female with 3-M syndrome that was caused by novel compound heterozygous mutations (c.4023-1 G>A in splice acceptor site of exon 22 and c.4359_4363dupGGCTG in exon 23) in the CUL7 gene (PMID:26488604)
• We report a family with variable phenotypic features of 3-M syndrome and we describe the prenatal and postnatal growth pattern of two affected sisters with a novel homozygous CUL7 mutation (c.3173-1G>C), showing a pre- and post-natal growth deficiency and a normal cranial circumference. (PMID:26850509)
• Cullin7 may serve as an indicator of poor prognosis in patients with epithelial ovarian cancer. (PMID:26962950)
• Hepatocellular carcinoma patients with positive expression for both Rabl3 and Cullin7 had a remarkably shorter survival time compared with patients with negative expression for both proteins. (PMID:28739496)
• Study shows that cullin 7 is highly expressed in breast cancer cells and suggests that positive expression is associated with the malignant phenotype and a predictor of poor prognosis. Cullin 7 is involved in cell proliferation and invasion by regulating the cell cycle and microtubule stability. (PMID:29207184)
• overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management. (PMID:29207970)
• CUL7 expression was associated with EC progression and poor prognosis. CUL7 may promote EMT via the ERKSNAI2 pathway in EC. (PMID:29393450)
• CUL7 prevents Caspase-8 activation by promoting Caspase-8 modification with non-degradative polyubiquitin chains at K215. CUL7 knockdown sensitized cancer cells to TRAIL-induced apoptosis in vitro and in nude mice. (PMID:30807646)
• Mutation in Cul7 gene is associated with 3M syndrome. (PMID:30945686)
• The mutational spectrum of CUL7, OBSL1, and investigation of genotype-phenotype correlation in 3M syndrome has been reported. (PMID:30980518)
• REVIEW: Cullin-RING E3 Ubiquitin Ligase 7 in Growth Control and Cancer (PMID:31898234)
• Identification of two CUL7 variants in two Chinese families with 3-M syndrome by whole-exome sequencing. (PMID:32141654)
• Cullin-7 (CUL7) is overexpressed in glioma cells and promotes tumorigenesis via NF-kappaB activation. (PMID:32252802)
• A novel mutation within intron 17 of the CUL7 gene results in appearance of premature termination codon. (PMID:32278698)
• A rare cause of syndromic short stature: 3M syndrome in three families. (PMID:33258289)
• Natural history of facial and skeletal features from neonatal period to adulthood in a 3M syndrome cohort with biallelic CUL7 or OBSL1 variants. (PMID:34597859)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cul7	ENSMUSG00000038545
rattus_norvegicus	Cul7	ENSRNOG00000017857

Paralogs (1): CUL9 (ENSG00000112659)

Protein

Protein identifiers

Cullin-7 — Q14999 (reviewed: Q14999)

All UniProt accessions (8): A0A669KAU7, A0A669KB95, A0A669KBH4, Q14999, A0A8I5KQF0, A0A8I5KS45, A0A8I5KUS3, A0A8I5KW87

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the 3M and Cul7-RING(FBXW8) complexes, which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer. The Cul7-RING(FBXW8) complex alone lacks ubiquitination activity and does not promote polyubiquitination and proteasomal degradation of p53/TP53. However it mediates recruitment of p53/TP53 for ubiquitination by neddylated CUL1-RBX1. Interaction with CUL9 is required to inhibit CUL9 activity and ubiquitination of BIRC5. The Cul7-RING(FBXW8) complex also mediates ubiquitination and consequent degradation of target proteins such as GORASP1, IRS1 and MAP4K1/HPK1. Ubiquitination of GORASP1 regulates Golgi morphogenesis and dendrite patterning in brain. Mediates ubiquitination and degradation of IRS1 in a mTOR-dependent manner: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2). The Cul7-RING(FBXW8) complex also mediates ubiquitination of MAP4K1/HPK1: recognizes and binds autophosphorylated MAP4K1/HPK1, leading to its degradation, thereby affecting cell proliferation and differentiation. Acts as a regulator in trophoblast cell epithelial-mesenchymal transition and placental development. While the Cul7-RING(FBXW8) and the 3M complexes are associated and involved in common processes, CUL7 and the Cul7-RING(FBXW8) complex may have additional functions. Probably plays a role in the degradation of proteins involved in endothelial proliferation and/or differentiation.

Subunit / interactions. Component of the 3M complex, composed of core components CUL7, CCDC8 and OBSL1. Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8. Within the Cul7-RING(FBXW8) complex interacts with FBXW8 and RBX1, but not with SKP1. Interacts with CUL1 (via the C-terminal domain); the interaction seems to be mediated by FBXW8; it is likely specific to FBXW8, but not other F-box proteins. Interacts (via the CPH domain) with p53/TP53; the interaction preferentially involves tetrameric and dimeric p53/TP53; this interaction recruits p53/TP53 for ubiquitination by neddylated CUL1-RBX1. The CUL7-CUL9 heterodimer seems to interact specifically with p53/TP53. Interacts with FBXW8; interaction is mutually exclusive of binding to CUL9 or p53/TP53. Interacts with CUL9; leading to inhibited CUL9 activity. Interacts with OBSL1. Interacts (as part of the 3M complex) with HDAC4 and HDAC5; it is negatively regulated by ANKRA2. (Microbial infection) Interacts with SV40 Large T antigen; this interaction seems to inhibit CUL7.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Perinuclear region. Golgi apparatus.

Tissue specificity. Highly expressed in fetal kidney and adult skeletal muscle. Also abundant in fetal brain, as well as in adult pancreas, kidney, placenta and heart. Detected in trophoblasts, lymphoblasts, osteoblasts, chondrocytes and skin fibroblasts.

Post-translational modifications. According to a report, may not be neddylated despite the conserved consensus site for neddylation at Lys-1576. Structural study of the Cul7-RING(FBXW8) reveals that both CUL7 and RBX1 are in orientations that are incompatible with neddylation.

Disease relevance. 3M syndrome 1 (3M1) [MIM:273750] An autosomal recessive disorder characterized by severe pre- and postnatal growth retardation, facial dysmorphism, large head circumference, and normal intelligence and endocrine function. Skeletal changes include long slender tubular bones and tall vertebral bodies. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The CPH domain is essential for interaction with p53/TP53.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the cullin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14999-1	1	yes
Q14999-2	2

RefSeq proteins (5): NP_001161842, NP_001361801, NP_001361802, NP_001361803, NP_055595* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004939	APC_su10/DOC_dom	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR014722	Rib_uL2_dom2	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR016158	Cullin_homology	Domain
IPR019559	Cullin_neddylation_domain	Domain
IPR021097	CPH_domain	Domain
IPR036317	Cullin_homology_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR045093	Cullin	Family
IPR055486	CUL7/CUL9_N	Domain
IPR056405	ARM_CUL7_CUL9	Domain
IPR059120	Cullin-like_AB	Domain

Pfam: PF03256, PF11515, PF23168, PF24742, PF26557

UniProt features (126 total): helix 61, strand 36, turn 9, sequence variant 8, region of interest 3, domain 2, splice variant 2, chain 1, mutagenesis site 1, compositionally biased region 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7Z8B	ELECTRON MICROSCOPY	2.8
2JNG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14999-F1	70.11	0.04

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 339, 1576

Mutagenesis-validated functional residues (1):

Position	Phenotype
389–404	abolishes interaction with tp53.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 356 (showing top): GOBP_MITOTIC_CYTOKINESIS, GOBP_DENDRITE_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (13): microtubule cytoskeleton organization (GO:0000226), mitotic cytokinesis (GO:0000281), vasculogenesis (GO:0001570), epithelial to mesenchymal transition (GO:0001837), placenta development (GO:0001890), proteolysis (GO:0006508), ubiquitin-dependent protein catabolic process (GO:0006511), Golgi organization (GO:0007030), regulation of mitotic nuclear division (GO:0007088), protein ubiquitination (GO:0016567), negative regulation of insulin receptor signaling pathway (GO:0046627), positive regulation of dendrite morphogenesis (GO:0050775), insulin receptor signaling pathway (GO:0008286)

GO Molecular Function (3): ubiquitin protein ligase binding (GO:0031625), ubiquitin ligase complex scaffold activity (GO:0160072), protein binding (GO:0005515)

GO Cellular Component (10): anaphase-promoting complex (GO:0005680), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), centrosome (GO:0005813), cytosol (GO:0005829), Cul7-RING ubiquitin ligase complex (GO:0031467), perinuclear region of cytoplasm (GO:0048471), 3M complex (GO:1990393), cytoskeleton (GO:0005856), cullin-RING ubiquitin ligase complex (GO:0031461)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
IRE1alpha activates chaperones	1
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
cullin-RING ubiquitin ligase complex	2
cytoskeleton organization	1
microtubule-based process	1
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
cell differentiation	1
blood vessel morphogenesis	1
mesenchymal cell differentiation	1
animal organ development	1
protein metabolic process	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
organelle organization	1
endomembrane system organization	1
regulation of mitotic cell cycle	1
regulation of cell cycle process	1
regulation of nuclear division	1
mitotic nuclear division	1
protein modification by small protein conjugation	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
positive regulation of cell morphogenesis	1
positive regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
positive regulation of neurogenesis	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
ubiquitin-like protein ligase binding	1
protein complex scaffold activity	1
binding	1
nuclear ubiquitin ligase complex	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

6163 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CUL7	FBXW8	Q8N3Y1	999
CUL7	RBX1	P62877	998
CUL7	SKP1	P34991	998
CUL7	OBSL1	O75147	997
CUL7	CUL2	Q13617	959
CUL7	CUL3	Q13618	958
CUL7	RNF7	Q9UBF6	954
CUL7	CUL4A	Q13619	954
CUL7	CCDC8	Q9H0W5	922
CUL7	FBXW11	Q9UKB1	915
CUL7	GLMN	Q92990	909
CUL7	CUL4B	Q13620	904
CUL7	CUL5	Q93034	895
CUL7	DDB1	Q16531	829
CUL7	UBA3	Q8TBC4	813

IntAct

133 interactions, top by confidence:

A	B	Type	Score
TP53	MDM2	psi-mi:“MI:0914”(association)	1.000
TP53	MDM4	psi-mi:“MI:0914”(association)	0.970
TP53	CUL7	psi-mi:“MI:0915”(physical association)	0.930
CUL7	TP53	psi-mi:“MI:0915”(physical association)	0.930
TP53	CUL7	psi-mi:“MI:0914”(association)	0.930
CUL9	TP53	psi-mi:“MI:0914”(association)	0.920
TP53	CDKN1A	psi-mi:“MI:0914”(association)	0.820
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
MAPK14	OBSL1	psi-mi:“MI:0914”(association)	0.790
TP53	CSNK2A2	psi-mi:“MI:0914”(association)	0.730
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
GLMN	CUL2	psi-mi:“MI:0914”(association)	0.640
CUL1	FBXO21	psi-mi:“MI:0914”(association)	0.600
OBSL1	CUL7	psi-mi:“MI:0915”(physical association)	0.540
OBSL1	CUL7	psi-mi:“MI:0407”(direct interaction)	0.540
LGALS3BP	RGPD8	psi-mi:“MI:0914”(association)	0.530
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
GLMN	CUL1	psi-mi:“MI:0914”(association)	0.530
CASQ2	PES1	psi-mi:“MI:0914”(association)	0.530

BioGRID (1016): AAAS (Affinity Capture-MS), ABCB1 (Affinity Capture-MS), ACAT1 (Affinity Capture-MS), ACIN1 (Affinity Capture-MS), ACLY (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), ACTN1 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), ACTR3 (Affinity Capture-MS), ADAR (Affinity Capture-MS), AHCY (Affinity Capture-MS), AHNAK (Affinity Capture-MS)

ESM2 similar proteins: A2AJ88, B3MRI9, B3NY03, B4H3U8, B4IL64, B4JLX2, B4L535, B4M709, B4N1W9, B4Q0P3, B5DKS8, D3ZEF4, O08703, O08962, O35219, O54853, P25848, P59111, P97414, Q02331, Q12809, Q14999, Q17QV9, Q21534, Q3TRM4, Q5BK26, Q5R667, Q5RCJ3, Q5RDS0, Q5TEA3, Q67E00, Q67E01, Q6CF18, Q6ZV29, Q7TNL3, Q7TT23, Q8IY17, Q8N2I9, Q8RY24, Q8VE73

Diamond homologs: D3ZEF4, O43149, O95714, Q14999, Q3U487, Q4U2R1, Q5RCJ3, Q5SSH7, Q5T447, Q80TT8, Q8IWT3, Q8VE73, Q9VR91, A2A5Z6, A6NED2, A9JRZ0, D3ZBM7, D3ZGQ5, E1C656, F1N6G5, F2Z461, F8W2M1, O74881, O75592, O95199, P0C5Y8, P14199, P18754, P23800, P34664, Q15034, Q1LZE1, Q24629, Q28BK1, Q2TAS2, Q3MHW0, Q3U0D9, Q4R828, Q52KW8, Q54VW7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NAE	“up-regulates activity”	CUL7	neddylation
CUL7	“form complex”	“Cullin 7-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	5	10.2×	9e-03
Cellular Senescence	7	9.6×	2e-03
Regulation of TP53 Activity through Phosphorylation	8	9.4×	2e-03
Signaling by ALK fusions and activated point mutants	6	9.0×	6e-03
Oxidative Stress Induced Senescence	8	7.2×	2e-03
Intracellular signaling by second messengers	7	6.4×	8e-03
Neddylation	11	5.2×	2e-03
Cellular responses to stimuli	12	3.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	5	24.4×	4e-04
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	5	24.4×	4e-04
regulation of heart rate	5	17.0×	1e-03
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	5	13.6×	3e-03
cellular senescence	5	10.7×	7e-03
long-term synaptic potentiation	5	10.2×	9e-03
protein ubiquitination	15	4.5×	4e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1044 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	72
Likely pathogenic	47
Uncertain significance	460
Likely benign	304
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012246	NM_014780.5(CUL7):c.3129G>A (p.Trp1043Ter)	Pathogenic
1027385	NM_014780.5(CUL7):c.4770_4773del (p.Cys1590fs)	Pathogenic
1069279	NM_014780.5(CUL7):c.2074C>T (p.Gln692Ter)	Pathogenic
1071560	NM_014780.5(CUL7):c.3907C>T (p.Gln1303Ter)	Pathogenic
1072812	NM_014780.5(CUL7):c.650del (p.Ser217fs)	Pathogenic
1074195	NM_014780.5(CUL7):c.4773+1G>A	Pathogenic
1224473	NM_014780.5(CUL7):c.3750_3762delinsGC (p.Ala1251fs)	Pathogenic
1264352	NM_014780.5(CUL7):c.2064-1G>A	Pathogenic
127244	NM_014780.5(CUL7):c.2592T>G (p.Tyr864Ter)	Pathogenic
1343072	NM_014780.5(CUL7):c.3421_3425delinsTTC (p.Arg1141fs)	Pathogenic
1383786	NM_014780.5(CUL7):c.4582C>T (p.Arg1528Ter)	Pathogenic
1402357	NM_014780.5(CUL7):c.3904C>T (p.Gln1302Ter)	Pathogenic
1403109	NM_014780.5(CUL7):c.3380G>A (p.Trp1127Ter)	Pathogenic
1413162	NM_014780.5(CUL7):c.679C>T (p.Gln227Ter)	Pathogenic
1414849	NM_014780.5(CUL7):c.1528C>T (p.Gln510Ter)	Pathogenic
1423528	NM_014780.5(CUL7):c.4759C>T (p.Gln1587Ter)	Pathogenic
1440040	NM_014780.5(CUL7):c.785C>A (p.Ser262Ter)	Pathogenic
1455425	NM_014780.5(CUL7):c.2667del (p.Thr890fs)	Pathogenic
1455666	NM_014780.5(CUL7):c.1484G>A (p.Trp495Ter)	Pathogenic
1613	NM_014780.5(CUL7):c.4333C>T (p.Arg1445Ter)	Pathogenic
1615	NM_014780.5(CUL7):c.4451_4452del (p.Val1484fs)	Pathogenic
1616	NM_014780.5(CUL7):c.4581dup (p.Arg1528fs)	Pathogenic
1618	NM_014780.5(CUL7):c.3379_3380del (p.Trp1127fs)	Pathogenic
1619	NM_014780.5(CUL7):c.1570-3C>A	Pathogenic
1687448	NM_014780.5(CUL7):c.4297C>T (p.Gln1433Ter)	Pathogenic
1705498	NM_014780.5(CUL7):c.2150_2151insA (p.Asn719fs)	Pathogenic
195894	NM_014780.5(CUL7):c.4717C>T (p.Arg1573Ter)	Pathogenic
197297	NM_014780.5(CUL7):c.898_919del (p.Met300fs)	Pathogenic
2017682	NM_014780.5(CUL7):c.4780dup (p.Glu1594fs)	Pathogenic
2021135	NM_014780.5(CUL7):c.2771dup (p.Asn924fs)	Pathogenic

SpliceAI

3743 predictions. Top by Δscore:

Variant	Effect	Δscore
6:43038263:CTAC:C	donor_loss	1.0000
6:43038264:TA:T	donor_loss	1.0000
6:43038265:A:AC	donor_gain	1.0000
6:43038266:C:CC	donor_gain	1.0000
6:43038266:CCAGA:C	donor_gain	1.0000
6:43038275:CAAG:C	donor_gain	1.0000
6:43038300:ATCT:A	donor_gain	1.0000
6:43038301:T:C	donor_gain	1.0000
6:43038564:ACCT:A	donor_gain	1.0000
6:43038565:CCTC:C	donor_gain	1.0000
6:43038567:T:TA	donor_gain	1.0000
6:43040287:T:TA	donor_gain	1.0000
6:43040526:TCA:T	donor_loss	1.0000
6:43040527:CACCT:C	donor_loss	1.0000
6:43040528:A:AC	donor_gain	1.0000
6:43040528:AC:A	donor_gain	1.0000
6:43040529:C:CG	donor_gain	1.0000
6:43040529:CC:C	donor_gain	1.0000
6:43040529:CCT:C	donor_gain	1.0000
6:43040529:CCTG:C	donor_gain	1.0000
6:43040529:CCTGT:C	donor_gain	1.0000
6:43040913:A:AC	donor_gain	1.0000
6:43040914:C:CC	donor_gain	1.0000
6:43040914:CT:C	donor_gain	1.0000
6:43040914:CTG:C	donor_gain	1.0000
6:43040914:CTGGT:C	donor_gain	1.0000
6:43041071:CTCAC:C	acceptor_gain	1.0000
6:43041072:TCAC:T	acceptor_gain	1.0000
6:43041073:CAC:C	acceptor_gain	1.0000
6:43041073:CACC:C	acceptor_gain	1.0000

AlphaMissense

11062 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:43046303:A:G	W865R	0.998
6:43046303:A:T	W865R	0.998
6:43052665:A:G	W42R	0.998
6:43052665:A:T	W42R	0.998
6:43046301:C:A	W865C	0.997
6:43046301:C:G	W865C	0.997
6:43052358:A:G	L144P	0.997
6:43052358:A:T	L144H	0.996
6:43050392:A:G	W414R	0.994
6:43050392:A:T	W414R	0.994
6:43052346:G:T	A148D	0.994
6:43052663:C:A	W42C	0.994
6:43052663:C:G	W42C	0.994
6:43052730:G:T	A20D	0.994
6:43046296:G:A	S867F	0.993
6:43046302:C:G	W865S	0.993
6:43046572:T:A	R809S	0.993
6:43046572:T:G	R809S	0.993
6:43052439:A:G	L117P	0.993
6:43045603:A:T	I949K	0.992
6:43046086:A:G	L889P	0.992
6:43048207:A:G	W704R	0.992
6:43048207:A:T	W704R	0.992
6:43050390:C:A	W414C	0.992
6:43050390:C:G	W414C	0.992
6:43051050:C:G	R384P	0.992
6:43052319:A:G	F157S	0.992
6:43052358:A:C	L144R	0.992
6:43052664:C:G	W42S	0.992
6:43045279:A:G	W996R	0.991

dbSNP variants (sampled 300 via entrez): RS1000285578 (6:43047520 A>C,T), RS1000334675 (6:43045013 G>A,T), RS1000434098 (6:43053884 G>A,C), RS1000445366 (6:43038164 C>G,T), RS1000465372 (6:43054079 A>C), RS1000509529 (6:43037447 A>G), RS1000651063 (6:43049334 A>G,T), RS1000719220 (6:43047760 A>G), RS1000837103 (6:43049005 C>T), RS1000889663 (6:43037147 C>G), RS1000931528 (6:43049226 C>T), RS1001021833 (6:43048970 C>T), RS1001162643 (6:43055172 G>A), RS1001426967 (6:43054951 G>A), RS1001617999 (6:43038995 A>G)

Disease associations

OMIM: gene MIM:609577 | disease phenotypes: MIM:273750

GenCC curated gene-disease

Disease	Classification	Inheritance
3M syndrome 1	Definitive	Autosomal recessive
3-M syndrome	Supportive	Autosomal recessive

Mondo (3): 3M syndrome 1 (MONDO:0010117), 3-M syndrome (MONDO:0007477), yakut short stature syndrome (MONDO:0800412)

Orphanet (1): 3M syndrome (Orphanet:2616)

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000179	Thick lower lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000574	Thick eyebrow
HP:0000682	Abnormal dental enamel morphology
HP:0000684	Delayed eruption of teeth
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000883	Thin ribs
HP:0000888	Horizontal ribs
HP:0000944	Abnormal metaphysis morphology
HP:0001249	Intellectual disability
HP:0001373	Joint dislocation

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90000025_51	Appendicular lean mass	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535314	Miller-McKusick-Malvaux-Syndrome (3M Syndrome) (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3805945	CUL7	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression	2
afuresertib	increases expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
ochratoxin A	decreases expression	1
coumarin	decreases phosphorylation	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Potassium Dichromate	increases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1UV	HAP1 CUL7 (-) 1	Cancer cell line	Male
CVCL_E1UW	HAP1 CUL7 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.