CYLD

Summary

CYLD (CYLD lysine 63 deubiquitinase, HGNC:2584) is a protein-coding gene on chromosome 16q12.1, encoding Ubiquitin carboxyl-terminal hydrolase CYLD (Q9NQC7). Deubiquitinase that specifically cleaves ‘Lys-63’- and linear ‘Met-1’-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-induced necroptosis. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is encodes a cytoplasmic protein with three cytoskeletal-associated protein-glycine-conserved (CAP-GLY) domains that functions as a deubiquitinating enzyme. Mutations in this gene have been associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 1540 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Brooke-Spiegler syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 427 total — 59 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 11 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001378743

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2584
Approved symbol	CYLD
Name	CYLD lysine 63 deubiquitinase
Location	16q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0849, USPL2
Ensembl gene	ENSG00000083799
Ensembl biotype	protein_coding
OMIM	605018
Entrez	1540

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 51 protein_coding, 4 retained_intron

ENST00000311559, ENST00000398568, ENST00000427738, ENST00000562884, ENST00000563629, ENST00000563976, ENST00000564326, ENST00000564634, ENST00000566024, ENST00000566206, ENST00000566679, ENST00000568704, ENST00000568744, ENST00000569418, ENST00000569891, ENST00000872834, ENST00000872835, ENST00000872836, ENST00000872837, ENST00000872838, ENST00000872839, ENST00000872840, ENST00000872841, ENST00000872842, ENST00000872843, ENST00000872844, ENST00000872845, ENST00000872846, ENST00000872847, ENST00000872848, ENST00000872849, ENST00000872850, ENST00000872851, ENST00000872852, ENST00000872853, ENST00000872854, ENST00000872855, ENST00000920611, ENST00000920612, ENST00000920613, ENST00000920614, ENST00000967675, ENST00000967676, ENST00000967677, ENST00000967678, ENST00000967679, ENST00000967680, ENST00000967681, ENST00000967682, ENST00000967683, ENST00000967684, ENST00000967685, ENST00000967686, ENST00000967687, ENST00000967688

RefSeq mRNA: 16 — MANE Select: NM_001378743 NM_001042355, NM_001042412, NM_001378743, NM_001378744, NM_001378745, NM_001378746, NM_001378747, NM_001378748, NM_001378749, NM_001378750, NM_001378751, NM_001378752, NM_001378753, NM_001378754, NM_001378755, NM_015247

CCDS: CCDS42164, CCDS45482

Canonical transcript exons

ENST00000427738 — 19 exons

Exon	Start	End
ENSE00000446017	50786855	50786946
ENSE00000446019	50791558	50791690
ENSE00000446022	50794212	50794428
ENSE00000683753	50787786	50787852
ENSE00001206701	50793546	50793664
ENSE00001206713	50792597	50792705
ENSE00001206771	50742762	50742841
ENSE00001373532	50796324	50801935
ENSE00001660649	50775166	50775174
ENSE00002589311	50742086	50742124
ENSE00003516554	50749576	50750202
ENSE00003521637	50779665	50780044
ENSE00003526216	50751604	50751906
ENSE00003550288	50777825	50777941
ENSE00003554224	50776179	50776277
ENSE00003599763	50781246	50781411
ENSE00003632865	50782325	50782466
ENSE00003669920	50784329	50784451
ENSE00003786887	50754319	50754424

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.9766 / max 508.2810, expressed in 1734 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154035	9.3861	1635
154036	5.0774	1331
154037	3.6241	952
154039	1.2925	418
154034	0.3205	168
154038	0.2760	111

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.42	gold quality
calcaneal tendon	UBERON:0003701	94.45	gold quality
lymph node	UBERON:0000029	94.42	gold quality
cartilage tissue	UBERON:0002418	94.28	gold quality
lateral globus pallidus	UBERON:0002476	94.22	gold quality
sperm	CL:0000019	94.18	gold quality
middle temporal gyrus	UBERON:0002771	93.91	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.89	gold quality
tonsil	UBERON:0002372	93.87	gold quality
substantia nigra pars compacta	UBERON:0001965	93.80	gold quality
leukocyte	CL:0000738	93.77	gold quality
bone marrow cell	CL:0002092	93.65	gold quality
mononuclear cell	CL:0000842	93.59	gold quality
monocyte	CL:0000576	93.58	gold quality
blood	UBERON:0000178	93.57	gold quality
gluteal muscle	UBERON:0002000	93.38	gold quality
corpus callosum	UBERON:0002336	93.24	gold quality
granulocyte	CL:0000094	93.23	gold quality
male germ cell	CL:0000015	93.17	gold quality
bone marrow	UBERON:0002371	93.02	gold quality
vermiform appendix	UBERON:0001154	92.88	gold quality
secondary oocyte	CL:0000655	92.72	gold quality
nipple	UBERON:0002030	92.65	gold quality
globus pallidus	UBERON:0001875	92.57	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.56	gold quality
medial globus pallidus	UBERON:0002477	92.54	gold quality
islet of Langerhans	UBERON:0000006	92.19	gold quality
middle frontal gyrus	UBERON:0002702	91.99	gold quality
colonic epithelium	UBERON:0000397	91.83	gold quality
CA1 field of hippocampus	UBERON:0003881	91.60	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.52
E-GEOD-150728	no	868.55

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO3, GLI1, LEF1, NFKB, SRF

miRNA regulators (miRDB)

215 targeting CYLD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4267	99.96	66.53	2368

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs) (PMID:12917689)
• inhibition of cylindromatosis tumour suppressor gene (CYLD) enhances activation of NF-kappaB; inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis (PMID:12917690)
• CYLD negatively regulates NF-kappaB signalling by deubiquitination; CYLD interacts with NEMO and TRAF2 (PMID:12917691)
• novel missense mutation in the CYLD gene, designated E474G in Brooke-Spiegler syndrome resembling trichoepithelioma (PMID:14632188)
• CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. (PMID:14676304)
• CYLD is induced by NF-kappaB (PMID:15226292)
• Mutations of the tumor suppressor gene CYLD at 16q12-q13 may give rise to familial trichoepithelioma indistinguishable from the phenotype assigned to 9p21. (PMID:15289313)
• Data show that the third cytoskeleton-associated protein-glycine conserved domain of CYLD specifically interacts with one of the two proline-rich sequences of NEMO/IKKgamma. (PMID:15341735)
• CYLD has a role in negative regulation of JNK signaling (PMID:15496400)
• findings suggest that CYLD serves as a novel target of IKK and that the site-specific phosphorylation of CYLD regulates its signaling function (PMID:15870263)
• The tumor suppressor familial cylindromatosis gene (CYLD) was found to be a direct target of BAF57 as determined by chromatin immunoprecipitation analysis. (CYLD) (PMID:16135788)
• study provided direct evidence for the negative regulation of Toll-like receptor 2 (TLR2) signaling by the tumor suppressor cylindromatosis (CYLD) (PMID:16230348)
• TRPA1 is a novel substrate for the de-ubiquitinating activity of CYLD, and this de-ubiquitination has the net effect of increasing the cellular pool of TRPA1 proteins. (PMID:16500080)
• The combined delivery of CYLD and TRAIL may be a new useful strategy for hepatocellular carcinoma or other tumor cells with enhanced NF-kappaB activity. (PMID:16627981)
• Mouse Cyld can negatively regulate different NF-kappaB pathways; inactivation of TRAF2 controls survival and inflammation, while inhibition of Bcl-3 controls proliferation and tumor growth. (PMID:16713561)
• Reduced expression of CYLD is associated with colon and hepatocellular carcinomas (PMID:16774947)
• additional function of CYLD could provide an explanation for the benign nature of most cylindroma lesions (PMID:17495026)
• in cell line KM-H2, a 2.35 Mb deletion was found at 16q12.1 putatively defining a small critical region for the recurrent 16q deletion in Hodgkin’s lymphoma. This region contains the CYLD gene, a known suppressor gene of the NF-mB pathway. (PMID:17606441)
• identifies CYLD for the first time as a critical negative regulator of host antiviral response (PMID:17608805)
• Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. (PMID:17609426)
• a heterozygous missense mutation c.1787 G > A (p.Gly596Asp, G596D) in CYLD exons was detected in a patient with multiple familial trichoepithelioma & affected family members; CYLD protein was not detected by staining in the trichoepithelioma tumour tissue (PMID:17662085)
• D681 in CYLD is required for cleavage of K63-linked polyubiquitin chains (PMID:17851586)
• study reports a novel CYLD gene mutation at nucleotide 2687 that carries out 1 amino acid change at glycine 896 in the 4 members of a family affected with trichoepithelioma but not in the proband (PMID:17875891)
• CYLD acts as a negative regulator for NF-kappaB-dependent inflammation in vivo, hence protecting the host against detrimental inflammatory response to NTHi infection (PMID:17925880)
• CYLD enhances tubulin polymerization into microtubules by lowering the critical concentration for microtubule assembly. (PMID:18222923)
• the role of CYLD in the pathogenesis of skin appendage tumours characterised by cylindromas, trichoepitheliomas and/or spiradenomas. (PMID:18234730)
• Report a novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma. (PMID:18242958)
• Potential role of CYLD (Cylindromatosis) as a deubiquitinating enzyme in vascular cells. (PMID:18245814)
• Results describe the crystal structure of the CYLD USP domain, revealing a distinctive architecture that provides molecular insights into its specificity toward Lys63-linked polyubiquitin. (PMID:18313383)
• These studies bring new insights into the molecular pathogenesis of S. pneumoniae infections through the NFAT-dependent mechanism and further identify CYLD as a negative regulator for NFAT signaling. (PMID:18332137)
• Loss of the UCH domain in CYLD may contribute to oncogenesis by enhancing the degradation of proteins that suppress cell proliferation or promote apoptosis. (PMID:18363762)
• Loss of CYLD might be associated with development of salivary gland tumors (PMID:18497946)
• Findings show that CYLD is a negative regulator of RIG-I-mediated innate antiviral response. (PMID:18636086)
• The mutation in the present case is novel and is predicted to alter the canonical splice acceptor sequence, thereby preventing proper splicing of the transcript. (PMID:19076795)
• cylindromatosis protein mutations, conformation, and physiologic roles in Brooke-Spiegler syndrome [REVIEW] (PMID:19462465)
• Results suggest that IKKepsilon and CYLD function as an oncogene-tumor suppressor network that participates in tumorigenesis. (PMID:19481526)
• CYLD negatively regulates tubulointertitial inflammatory responses via suppressing activation of JNK in tubular epithelial cells, putatively attenuating the progressive tubulointerstitial lesions in IgA nephropathy. (PMID:19800320)
• Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas (PMID:19807742)
• CYLD controls cell growth and division at the G(1)/S-phase as well as cytokinesis by associating with alpha-tubulin and microtubules through its CAP-Gly domains. (PMID:19893491)
• A novel missense mutation in a Chinese family with multiple familial trichoepithelioma (PMID:19911186)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyld	ENSDARG00000060058
mus_musculus	Cyld	ENSMUSG00000036712
rattus_norvegicus	Cyld	ENSRNOG00000014048
drosophila_melanogaster	CYLD	FBGN0032210
caenorhabditis_elegans		WBGENE00009594

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase CYLD — Q9NQC7 (reviewed: Q9NQC7)

Alternative names: Deubiquitinating enzyme CYLD, Ubiquitin thioesterase CYLD, Ubiquitin-specific-processing protease CYLD

All UniProt accessions (7): Q9NQC7, H3BPZ5, H3BS09, H3BSW9, I3L117, J3KRR7, J3QKR2

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase that specifically cleaves ‘Lys-63’- and linear ‘Met-1’-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-induced necroptosis. Negatively regulates NF-kappa-B activation by deubiquitinating upstream signaling factors. Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation. Negative regulator of Wnt signaling. Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules. Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis. Required for normal cell cycle progress and normal cytokinesis. Inhibits nuclear translocation of NF-kappa-B. Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation. Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells. Negatively regulates TNFRSF11A signaling and osteoclastogenesis. Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation. Ability to remove linear (‘Met-1’-linked) polyubiquitin chains regulates innate immunity and TNF-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins. Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation. Involved in TNF-induced necroptosis by removing linear (‘Met-1’-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1. Negatively regulates intestinal inflammation by removing ‘Lys-63’ linked polyubiquitin chain of NLRP6, thereby reducing the interaction between NLRP6 and PYCARD/ASC and formation of the NLRP6 inflammasome. Does not catalyze deubiquitination of heterotypic ‘Lys-63’-/‘Lys-48’-linked branched ubiquitin chains. Removes ‘Lys-63’ linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades. Also removes ‘Lys-63’-linked polyubiquitin chains of MAP3K1 and MA3P3K3, which inhibit their interaction with MAP2K1 and MAP2K2.

Subunit / interactions. Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region). Interacts with TRAF2 and TRIP. Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and RIGI. Interacts (via CAP-Gly domain) with microtubules. Interacts with HDAC6 and BCL3. Interacts with MAP3K7. Identified in a complex with TRAF6 and SQSTM1. Interacts with OPTN and SQSTM1. Interacts with CEP350. Interacts with RNF31; the interaction is indirect and is mediated via SPATA2. Interacts with SPATA2 (via the PUB domain); the interaction is direct and recruits CYLD to the LUBAC complex, thereby regulating TNF-induced necroptosis.

Subcellular location. Cytoplasm. Perinuclear region. Cytoskeleton. Cell membrane. Microtubule organizing center. Centrosome. Spindle. Cilium basal body.

Tissue specificity. Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney.

Post-translational modifications. Ubiquitinated. Polyubiquitinated in hepatocytes treated with palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads to proteasomal degradation. Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B.

Disease relevance. Cylindromatosis, familial (FCYL) [MIM:132700] A disorder characterized by multiple skin tumors that develop from skin appendages, such as hair follicles and sweat glands. Affected individuals typically develop large numbers of tumors called cylindromas that arise predominantly in hairy parts of the body with approximately 90% on the head and neck. In severely affected individuals, cylindromas may combine into a confluent mass which may ulcerate or become infected (turban tumor syndrome). Individuals with familial cylindromatosis occasionally develop other types of tumors including spiradenomas that begin in sweat glands, and trichoepitheliomas arising from hair follicles. The disease is caused by variants affecting the gene represented in this entry. Trichoepithelioma, multiple familial, 1 (MFT1) [MIM:601606] An autosomal dominant dermatosis characterized by the presence of many skin tumors predominantly on the face. Since histologic examination shows dermal aggregates of basaloid cells with connection to or differentiation toward hair follicles, this disorder has been thought to represent a benign hamartoma of the pilosebaceous apparatus. Trichoepitheliomas can degenerate into basal cell carcinoma. The disease is caused by variants affecting the gene represented in this entry. Brooke-Spiegler syndrome (BRSS) [MIM:605041] An autosomal dominant disorder characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, and gradually increase in size and number throughout life. The disease is caused by variants affecting the gene represented in this entry. Frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (FTDALS8) [MIM:619132] A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. FTDALS8 is an autosomal dominant form. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by phosphorylation at serine residues.

Similarity. Belongs to the peptidase C19 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NQC7-1	1	yes
Q9NQC7-2	2

RefSeq proteins (16): NP_001035814, NP_001035877, NP_001365672, NP_001365673, NP_001365674, NP_001365675, NP_001365676, NP_001365677, NP_001365678, NP_001365679, NP_001365680, NP_001365681, NP_001365682, NP_001365683, NP_001365684, NP_056062 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000938	CAP-Gly_domain	Domain
IPR001394	Peptidase_C19_UCH	Domain
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR036859	CAP-Gly_dom_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily

Pfam: PF00443, PF01302, PF16607

UniProt features (120 total): strand 41, helix 23, mutagenesis site 18, binding site 8, turn 7, region of interest 6, sequence variant 5, domain 4, modified residue 3, active site 2, chain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7OWD	X-RAY DIFFRACTION	1.71
7OWC	X-RAY DIFFRACTION	1.85
2VHF	X-RAY DIFFRACTION	2.8
1IXD	SOLUTION NMR
1WHL	SOLUTION NMR
1WHM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQC7-F1	75.06	0.43

Functional residue map

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

Catalytic / active sites (2): 601 (nucleophile); 871 (proton acceptor)

Ligand- & substrate-binding residues (8): 788; 791; 799; 802; 817; 820; 825; 833

Post-translational modifications (3): 387, 418, 422

Mutagenesis-validated functional residues (18):

Position	Phenotype
418	reduced phosphorylation; when associated with a-422; a-432 and a-436. loss of phosphorylation; when associated with a-42
418	abolishes deubiquitination of traf2; when associated with e-422; e-432; e-436; e-439; e-441 and e-444.
422	reduced phosphorylation; when associated with a-418; a-432 and a-436. loss of phosphorylation; when associated with a-41
422	abolishes deubiquitination of traf2; when associated with e-418; e-432; e-436; e-439; e-441 and e-444.
432	slightly reduced phosphorylation; when associated with a-436. reduced phosphorylation; when associated with a-418; a-422
432	abolishes deubiquitination of traf2; when associated with e-418; e-422; e-436; e-439; e-441 and e-444.
436	slightly reduced phosphorylation; when associated with a-432. reduced phosphorylation; when associated with a-418; a-422
436	abolishes deubiquitination of traf2; when associated with e-418; e-422; e-432; e-439; e-441 and e-444.
439	loss of phosphorylation; when associated with a-418; a-422; a-432; a-436; a-441 and a-444.
439	abolishes deubiquitination of traf2; when associated with e-418; e-422; e-432; e-436; e-441 and e-444.
441	loss of phosphorylation; when associated with a-418; a-422; a-432; a-436; a-439 and a-444.
441	abolishes deubiquitination of traf2; when associated with e-418; e-422; e-432; e-436; e-439 and e-444.
444	loss of phosphorylation; when associated with a-418; a-422; a-432; a-436; a-439 and a-441.
444	abolishes deubiquitination of traf2; when associated with e-418; e-422; e-432; e-436; e-439 and e-441.
457	abolishes binding to traf2.
601	loss of deubiquitinating activity.
622	impaired interaction with spata2.
871	loss of deubiquitinating activity.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling

MSigDB gene sets: 535 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, ATF_B, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, CREL_01, REACTOME_INNATE_IMMUNE_SYSTEM, MYOGENIN_Q6, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_INFLAMMATORY_RESPONSE, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (36): proteolysis (GO:0006508), regulation of mitotic cell cycle (GO:0007346), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), Wnt signaling pathway (GO:0016055), protein deubiquitination (GO:0016579), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), negative regulation of type I interferon production (GO:0032480), nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway (GO:0035872), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), CD4-positive or CD8-positive, alpha-beta T cell lineage commitment (GO:0043369), innate immune response (GO:0045087), regulation of B cell differentiation (GO:0045577), positive regulation of T cell differentiation (GO:0045582), negative regulation of JNK cascade (GO:0046329), homeostasis of number of cells (GO:0048872), regulation of inflammatory response (GO:0050727), negative regulation of inflammatory response (GO:0050728), positive regulation of T cell receptor signaling pathway (GO:0050862), regulation of necroptotic process (GO:0060544), necroptotic process (GO:0070266), regulation of microtubule cytoskeleton organization (GO:0070507), protein K63-linked deubiquitination (GO:0070536), negative regulation of canonical Wnt signaling pathway (GO:0090090), ripoptosome assembly involved in necroptotic process (GO:1901026), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223), regulation of cilium assembly (GO:1902017), negative regulation of p38MAPK cascade (GO:1903753), positive regulation of protein localization (GO:1903829), protein linear deubiquitination (GO:1990108), negative regulation of interleukin-18-mediated signaling pathway (GO:2000493), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), regulation of intrinsic apoptotic signaling pathway (GO:2001242), immune system process (GO:0002376), canonical NF-kappaB signal transduction (GO:0007249), defense response to bacterium (GO:0042742), positive regulation of canonical NF-kappaB signal transduction (GO:0043123)

GO Molecular Function (12): cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), K63-linked deubiquitinase activity (GO:0061578), Met1-linked polyubiquitin deubiquitinase activity (GO:0061815), proline-rich region binding (GO:0070064), K48-linked deubiquitinase activity (GO:1990380), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (21): nucleoplasm (GO:0005654), centrosome (GO:0005813), spindle (GO:0005819), cytosol (GO:0005829), microtubule (GO:0005874), plasma membrane (GO:0005886), centriolar satellite (GO:0034451), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), perinuclear region of cytoplasm (GO:0048471), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), ciliary tip (GO:0097542), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cytoplasmic microtubule (GO:0005881), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020), midbody (GO:0030496), cell projection (GO:0042995), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
TNF signaling	3
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Deubiquitination	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	12
deubiquitinase activity	3
cytoplasm	3
cilium	3
cysteine-type deubiquitinase activity	2
inflammatory response	2
microtubule organizing center	2
microtubule cytoskeleton	2
intracellular membraneless organelle	2
sperm flagellum	2
protein metabolic process	1
mitotic cell cycle	1
regulation of cell cycle	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
cell surface receptor signaling pathway	1
protein modification by small protein removal	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
cytoplasmic pattern recognition receptor signaling pathway	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
T cell lineage commitment	1
positive T cell selection	1
immune response	1
defense response to symbiont	1
B cell differentiation	1
regulation of lymphocyte differentiation	1
regulation of B cell activation	1
T cell differentiation	1
regulation of T cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of T cell activation	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
multicellular organismal-level homeostasis	1
regulation of defense response	1

Protein interactions and networks

STRING

2250 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYLD	THOC2	Q8NI27	992
CYLD	IKBKG	Q9Y6K9	992
CYLD	TRADD	Q15628	991
CYLD	THOC3	Q96J01	989
CYLD	GLI2	P10070	988
CYLD	TRAF6	Q9Y4K3	974
CYLD	RIPK1	Q13546	970
CYLD	THOC1	Q96FV9	962
CYLD	RNF31	Q96EP0	909
CYLD	TNFRSF1A	P19438	906
CYLD	FADD	Q13158	889
CYLD	SPATA2	Q9UM82	880
CYLD	BIRC2	Q13490	879
CYLD	ITCH	Q96J02	870
CYLD	BIRC3	Q13489	858

IntAct

103 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
E6	TP53	psi-mi:“MI:0914”(association)	0.840
E6	TP53	psi-mi:“MI:0914”(association)	0.810
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
CYLD	TUBA1A	psi-mi:“MI:0915”(physical association)	0.580
TUBA1A	CYLD	psi-mi:“MI:0915”(physical association)	0.580
HDAC6	CYLD	psi-mi:“MI:0915”(physical association)	0.580
CYLD	TUBA1A	psi-mi:“MI:0403”(colocalization)	0.580
CYLD	HDAC6	psi-mi:“MI:0915”(physical association)	0.580
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
CYLD	SPATA2	psi-mi:“MI:0915”(physical association)	0.560
CYLD	IKBKG	psi-mi:“MI:0915”(physical association)	0.550
SPATA2	CASK	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
FGL2	PCNT	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530

BioGRID (1154): CYLD (Affinity Capture-Western), CEP350 (Affinity Capture-Western), MAPRE1 (Affinity Capture-Western), CYLD (Affinity Capture-Western), CYLD (Reconstituted Complex), MAPRE1 (Phenotypic Enhancement), CYLD (Two-hybrid), TRAF6 (Affinity Capture-Western), CYLD (Affinity Capture-Western), CLIP3 (Affinity Capture-Western), CYLD (Affinity Capture-Western), MIB2 (Affinity Capture-Western), MIB2 (Affinity Capture-MS), CYLD (Biochemical Activity), CYLD (Affinity Capture-MS)

ESM2 similar proteins: A0JM59, A2BGT0, A5PJS6, A5PMR2, A5PN09, A6QNM7, A7Z056, B1AY15, B1WBD7, D2HBJ8, E1C213, E7F6T8, E9QG68, O88974, P52479, Q0V9G5, Q14694, Q15047, Q1RMU2, Q28CN3, Q2KJ09, Q2NL57, Q3KR59, Q5R5Z6, Q5RED8, Q5REG5, Q5XGZ2, Q5ZJN4, Q66H62, Q6NTR6, Q6P549, Q70CQ3, Q70CQ4, Q70EK9, Q7ZUM8, Q7ZXR7, Q80TQ2, Q8BW70, Q8C0R0, Q8C2S0

Diamond homologs: Q1RMU2, Q5RED8, Q66H62, Q80TQ2, Q9NQC7

SIGNOR signaling

30 interactions.

A	Effect	B	Mechanism
CYLD	down-regulates	TRAF6	deubiquitination
CYLD	“down-regulates activity”	TRAF2	deubiquitination
CYLD	down-regulates	BCL3	deubiquitination
CYLD	up-regulates	CCND1
CHUK	“down-regulates activity”	CYLD	phosphorylation
CHUK	“up-regulates activity”	CYLD	phosphorylation
IKBKB	“down-regulates activity”	CYLD	phosphorylation
IKBKB	“up-regulates activity”	CYLD	phosphorylation
CAMK2B	“up-regulates activity”	CYLD	phosphorylation
CAMK2B	up-regulates	CYLD	phosphorylation
CAMK2A	“up-regulates activity”	CYLD	phosphorylation
IKK-complex	“down-regulates activity”	CYLD	phosphorylation
IKBKE	“down-regulates activity”	CYLD	phosphorylation
CYLD	“up-regulates activity”	MAP3K7	deubiquitination
TRIM47	“down-regulates quantity”	CYLD	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Activation of BAD and translocation to mitochondria	7	72.0×	8e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	63.5×	1e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	63.5×	1e-09
Activation of BH3-only proteins	7	47.0×	7e-09
Regulation of NF-kappa B signaling	5	42.9×	3e-06
TNFR1-induced NF-kappa-B signaling pathway	7	31.8×	1e-07
Negative regulators of DDX58/IFIH1 signaling	7	30.9×	1e-07
TRAF6 mediated NF-kB activation	5	30.9×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic pattern recognition receptor signaling pathway	5	48.7×	2e-05
positive regulation of interferon-alpha production	5	35.6×	8e-05
protein targeting	5	20.1×	8e-04
canonical NF-kappaB signal transduction	5	20.1×	8e-04
intracellular protein localization	12	13.8×	6e-08
obsolete positive regulation of NF-kappaB transcription factor activity	6	13.6×	8e-04
antiviral innate immune response	5	12.5×	5e-03
response to virus	7	11.1×	8e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 11 cancer types — BLCA, BRCA, COADREAD, HNSC, NPC, NSCLC, PCM, PROSTATE, RCC, STOMACH, THYM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	9
Uncertain significance	212
Likely benign	51
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2633029	NM_001378743.1(CYLD):c.2263C>T (p.Gln755Ter)	Pathogenic
267228	NM_001378743.1(CYLD):c.831_834del (p.Asp277fs)	Pathogenic
267229	NM_001378743.1(CYLD):c.911dup (p.Ala305fs)	Pathogenic
267230	NM_001378743.1(CYLD):c.968_977del (p.Ser323fs)	Pathogenic
267231	NM_001378743.1(CYLD):c.987_988dup (p.Gly330fs)	Pathogenic
267232	NM_001378743.1(CYLD):c.1112C>A (p.Ser371Ter)	Pathogenic
267233	NM_001378743.1(CYLD):c.1327C>T (p.Gln443Ter)	Pathogenic
267234	NM_001378743.1(CYLD):c.1363C>T (p.Gln455Ter)	Pathogenic
267235	NM_001378743.1(CYLD):c.1537dup (p.Cys513fs)	Pathogenic
267236	NM_001378743.1(CYLD):c.1599dup (p.Val534fs)	Pathogenic
267237	NM_001378743.1(CYLD):c.1658_1661del (p.Asn553fs)	Pathogenic
267240	NM_001378743.1(CYLD):c.1771A>T (p.Lys591Ter)	Pathogenic
267243	NM_001378743.1(CYLD):c.1950-2_1953del	Pathogenic
267245	NM_001378743.1(CYLD):c.2108G>A (p.Arg703Lys)	Pathogenic
267246	NM_001378743.1(CYLD):c.2138_2139dup (p.Phe714fs)	Pathogenic
267247	NM_001378743.1(CYLD):c.2242-2A>G	Pathogenic
267249	NM_001378743.1(CYLD):c.2299A>T (p.Lys767Ter)	Pathogenic
267251	NM_001378743.1(CYLD):c.2350+1G>T	Pathogenic
267253	NM_001378743.1(CYLD):c.2406_2407del (p.Cys802_Tyr803delinsTer)	Pathogenic
267254	NM_001378743.1(CYLD):c.2515del (p.Ser839fs)	Pathogenic
3067806	NM_001378743.1(CYLD):c.890_892delinsGT (p.Leu297fs)	Pathogenic
3068572	NM_001378743.1(CYLD):c.2039A>G (p.Lys680Arg)	Pathogenic
3642384	NM_001378743.1(CYLD):c.2215_2241+289del	Pathogenic
3652898	NM_001378743.1(CYLD):c.1840_1843del (p.Ser614fs)	Pathogenic
3655472	NM_001378743.1(CYLD):c.1094C>A (p.Ser365Ter)	Pathogenic
3657026	NM_001378743.1(CYLD):c.2516C>G (p.Ser839Ter)	Pathogenic
3657926	NM_001378743.1(CYLD):c.1126dup (p.Tyr376fs)	Pathogenic
3664310	NM_001378743.1(CYLD):c.1930del (p.Ile644fs)	Pathogenic
3722188	NM_001378743.1(CYLD):c.2119C>T (p.Gln707Ter)	Pathogenic
3722189	NM_001378743.1(CYLD):c.2288_2289del (p.Asp762_Phe763insTer)	Pathogenic

SpliceAI

3236 predictions. Top by Δscore:

Variant	Effect	Δscore
16:50742760:A:AG	acceptor_gain	1.0000
16:50742761:G:GA	acceptor_gain	1.0000
16:50742838:ACAG:A	donor_gain	1.0000
16:50751595:A:AG	acceptor_gain	1.0000
16:50751737:A:T	donor_gain	1.0000
16:50754420:CCCAG:C	donor_loss	1.0000
16:50754421:CCAGG:C	donor_loss	1.0000
16:50754423:AGG:A	donor_loss	1.0000
16:50754425:GT:G	donor_loss	1.0000
16:50754426:T:G	donor_loss	1.0000
16:50777822:TAG:T	acceptor_loss	1.0000
16:50777949:G:GG	donor_gain	1.0000
16:50781245:GGAA:G	acceptor_gain	1.0000
16:50781395:GCGCT:G	donor_gain	1.0000
16:50782309:A:AG	acceptor_gain	1.0000
16:50782310:A:G	acceptor_gain	1.0000
16:50782321:TCA:T	acceptor_loss	1.0000
16:50782322:CAG:C	acceptor_loss	1.0000
16:50782323:A:AG	acceptor_gain	1.0000
16:50782324:G:GC	acceptor_gain	1.0000
16:50782324:GC:G	acceptor_gain	1.0000
16:50782324:GCA:G	acceptor_gain	1.0000
16:50782467:G:GG	donor_gain	1.0000
16:50784327:A:AC	acceptor_loss	1.0000
16:50784327:A:AG	acceptor_gain	1.0000
16:50784328:G:GC	acceptor_gain	1.0000
16:50784328:GC:G	acceptor_gain	1.0000
16:50784328:GCT:G	acceptor_gain	1.0000
16:50784328:GCTT:G	acceptor_gain	1.0000
16:50784328:GCTTA:G	acceptor_gain	1.0000

AlphaMissense

6293 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:50749828:G:A	G44R	1.000
16:50749828:G:C	G44R	1.000
16:50749829:G:A	G44E	1.000
16:50749837:G:A	G47R	1.000
16:50749837:G:C	G47R	1.000
16:50749838:G:A	G47E	1.000
16:50749997:T:C	L100P	1.000
16:50750024:G:T	R109M	1.000
16:50750128:G:A	G144R	1.000
16:50750128:G:C	G144R	1.000
16:50750129:G:A	G144E	1.000
16:50750135:T:A	V146E	1.000
16:50750188:G:A	G164R	1.000
16:50750188:G:C	G164R	1.000
16:50750189:G:A	G164E	1.000
16:50750192:T:A	V165D	1.000
16:50750198:T:C	L167S	1.000
16:50750198:T:G	L167W	1.000
16:50751622:G:C	G175R	1.000
16:50751623:G:A	G175D	1.000
16:50751634:G:A	G179R	1.000
16:50751634:G:C	G179R	1.000
16:50751634:G:T	G179W	1.000
16:50751635:G:A	G179E	1.000
16:50751635:G:T	G179V	1.000
16:50751658:T:C	F187L	1.000
16:50751659:T:C	F187S	1.000
16:50751660:T:A	F187L	1.000
16:50751660:T:G	F187L	1.000
16:50751680:G:A	G194D	1.000

dbSNP variants (sampled 300 via entrez): RS1000008258 (16:50778175 T>A,C), RS1000039188 (16:50757073 A>C), RS1000053726 (16:50768338 CTT>C,CT), RS1000096008 (16:50783585 C>T), RS1000122348 (16:50742688 G>A), RS1000170505 (16:50771583 T>C), RS1000210822 (16:50798388 C>A), RS1000259826 (16:50743568 C>T), RS1000279381 (16:50783266 T>C), RS1000424955 (16:50783721 T>C), RS1000446499 (16:50778684 G>A), RS1000486296 (16:50758577 G>A), RS1000642452 (16:50749148 A>G), RS1000643155 (16:50755580 T>C), RS1000656037 (16:50766828 A>G)

Disease associations

OMIM: gene MIM:605018 | disease phenotypes: MIM:132700, MIM:605041, MIM:601606, MIM:619132, MIM:167000, MIM:300896, MIM:186580, MIM:609464

GenCC curated gene-disease

Disease	Classification	Inheritance
Brooke-Spiegler syndrome	Definitive	Autosomal dominant
familial cylindromatosis	Definitive	Autosomal dominant
frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Strong	Autosomal dominant
trichoepithelioma, multiple familial, 1	Strong	Autosomal dominant
familial multiple trichoepithelioma	Supportive	Autosomal dominant
amyotrophic lateral sclerosis	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Brooke-Spiegler syndrome	Definitive	AD
frontotemporal dementia and/or amyotrophic lateral sclerosis 8	Limited	AD

Mondo (10): familial cylindromatosis (MONDO:0007565), Brooke-Spiegler syndrome (MONDO:0011512), trichoepithelioma, multiple familial, 1 (MONDO:0042977), frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (MONDO:0030872), familial multiple trichoepithelioma (MONDO:0011114), ovarian cancer (MONDO:0008170), SLC35A2-congenital disorder of glycosylation (MONDO:0010478), Blau syndrome (MONDO:0008523), hereditary neoplastic syndrome (MONDO:0015356), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (8): Familial cylindromatosis (Orphanet:211), Brooke-Spiegler syndrome (Orphanet:79493), Familial multiple trichoepithelioma (Orphanet:867), Rare ovarian cancer (Orphanet:213500), SLC35A2-CDG (Orphanet:356961), Blau syndrome (Orphanet:90340), Inherited cancer-predisposing syndrome (Orphanet:140162), Early-onset sarcoidosis (Orphanet:90341)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000708	Atypical behavior
HP:0000726	Dementia
HP:0001056	Milia
HP:0001482	Subcutaneous nodule
HP:0002145	Frontotemporal dementia
HP:0002185	Neurofibrillary tangles
HP:0002283	Global brain atrophy
HP:0002354	Memory impairment
HP:0002381	Aphasia
HP:0002442	Dyscalculia
HP:0002664	Neoplasm
HP:0002671	Basal cell carcinoma
HP:0003581	Adult onset
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0007354	Amyotrophic lateral sclerosis
HP:0008069	Neoplasm of the skin
HP:0010529	Echolalia
HP:0011462	Young adult onset
HP:0033051	Impaired executive functioning
HP:0100585	Telangiectasia of the skin
HP:0200034	Papule

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001292_3	Leprosy	2.000000e-10
GCST001438_12	Crohn’s disease	1.000000e-37
GCST001482_29	Lumbar spine bone mineral density	2.000000e-10
GCST002772_10	Leprosy	5.000000e-06
GCST002772_22	Leprosy	4.000000e-11
GCST004131_18	Inflammatory bowel disease	1.000000e-38
GCST004132_6	Crohn’s disease	6.000000e-99
GCST004904_243	Body mass index	1.000000e-08
GCST005795_4	Femoral neck bone mineral density	4.000000e-07
GCST005796_28	Lumbar spine bone mineral density	8.000000e-09
GCST006979_656	Heel bone mineral density	7.000000e-10
GCST007324_7	Adventurousness	3.000000e-11
GCST007325_127	General risk tolerance (MTAG)	5.000000e-11
GCST007995_1	Asthma (childhood onset)	4.000000e-08
GCST008838_4	Asthma (time to onset)	4.000000e-08
GCST012020_155	Serum metabolite levels	2.000000e-11
GCST012021_80	Serum metabolite levels	2.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007785	femoral neck bone mineral density
EFO:0007701	spine bone mineral density
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0004847	age at onset

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
C538157	Blau syndrome (supp.)
C536611	Familial cylindromatosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630858 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

73 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
sodium arsenite	affects cotreatment, increases abundance, affects reaction, increases expression, affects methylation	4
Cyclosporine	affects cotreatment, increases expression, decreases expression	4
Cisplatin	affects cotreatment, decreases expression, increases expression, increases response to substance	3
moringin	affects cotreatment, increases expression, decreases expression	2
bisphenol A	decreases expression, decreases methylation	2
Cannabidiol	affects cotreatment, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
Glupearl 19S	increases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
methylselenic acid	increases expression	1
sodium bichromate	increases expression	1
cypermethrin	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	decreases expression	1
nefazodone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
RTKI cpd	increases expression	1
U 0126	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4605990	Binding	Inhibition of human 6His-tagged CYLD expressed in baculovirus infected Sf21 insect cells assessed as cleavage of Ubiquitin-Rhodamine110-glycine to Ubiquitin and Rhodamine110-glycine using Ubiquitin-Rhodamine110-glycine as substrate by fluor	Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8EH	Abcam HCT 116 CYLD KO	Cancer cell line	Male
CVCL_B8UK	Abcam MCF-7 CYLD KO	Cancer cell line	Female
CVCL_B9GQ	Abcam A-549 CYLD KO	Cancer cell line	Male
CVCL_D7NA	Ubigene A-549 CYLD KO	Cancer cell line	Male
CVCL_D8JS	Ubigene HCT 116 CYLD KO	Cancer cell line	Male
CVCL_D9CV	Ubigene HEK293 CYLD KO	Transformed cell line	Female
CVCL_E0BG	Ubigene HeLa CYLD KO	Cancer cell line	Female
CVCL_SK24	HAP1 CYLD (-) 1	Cancer cell line	Male
CVCL_SK25	HAP1 CYLD (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS