FBXW8

Summary

FBXW8 (F-box and WD repeat domain containing 8, HGNC:13597) is a protein-coding gene on chromosome 12q24.22, encoding F-box/WD repeat-containing protein 8 (Q8N3Y1). Substrate-recognition component of the Cul7-RING(FBXW8) ubiquitin ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene contains a WD-40 domain, in addition to an F-box motif, so it belongs to the Fbw class. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 26259 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 114 total
• MANE Select transcript: NM_153348

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13597
Approved symbol	FBXW8
Name	F-box and WD repeat domain containing 8
Location	12q24.22
Locus type	gene with protein product
Status	Approved
Aliases	FBX29, FBW6, FBW8
Ensembl gene	ENSG00000174989
Ensembl biotype	protein_coding
OMIM	609073
Entrez	26259

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000309909, ENST00000455858, ENST00000551773, ENST00000652555, ENST00000877976, ENST00000877977, ENST00000917719, ENST00000917720, ENST00000917721, ENST00000971031, ENST00000971032, ENST00000971033, ENST00000971034

RefSeq mRNA: 2 — MANE Select: NM_153348 NM_012174, NM_153348

CCDS: CCDS44988, CCDS9182

Canonical transcript exons

ENST00000652555 — 11 exons

Exon	Start	End
ENSE00000755690	117024147	117024320
ENSE00000755691	117027394	117027504
ENSE00000835048	116928023	116928127
ENSE00000835049	116945364	116945528
ENSE00000835050	116949618	116949706
ENSE00000835052	117010323	117010450
ENSE00001258642	116988663	116988869
ENSE00001258654	116985206	116985402
ENSE00001258664	116964697	116964854
ENSE00001258689	117028028	117031148
ENSE00001310679	116910950	116911355

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 86.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1509 / max 212.9012, expressed in 1782 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128253	14.1509	1782

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	86.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.47	gold quality
ventricular zone	UBERON:0003053	82.15	gold quality
bone marrow cell	CL:0002092	80.57	gold quality
islet of Langerhans	UBERON:0000006	80.34	gold quality
ganglionic eminence	UBERON:0004023	79.59	gold quality
embryo	UBERON:0000922	79.58	gold quality
adrenal tissue	UBERON:0018303	77.96	gold quality
pancreas	UBERON:0001264	77.72	gold quality
colonic epithelium	UBERON:0000397	77.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.40	gold quality
popliteal artery	UBERON:0002250	77.32	gold quality
tibial artery	UBERON:0007610	77.30	gold quality
mucosa of stomach	UBERON:0001199	77.20	gold quality
smooth muscle tissue	UBERON:0001135	76.96	gold quality
body of pancreas	UBERON:0001150	76.94	gold quality
adenohypophysis	UBERON:0002196	76.87	gold quality
left lobe of thyroid gland	UBERON:0001120	76.77	gold quality
right lobe of thyroid gland	UBERON:0001119	76.72	gold quality
calcaneal tendon	UBERON:0003701	76.69	gold quality
cortical plate	UBERON:0005343	76.48	gold quality
left ovary	UBERON:0002119	76.25	gold quality
right ovary	UBERON:0002118	76.18	gold quality
aorta	UBERON:0000947	76.16	gold quality
body of uterus	UBERON:0009853	75.96	gold quality
thyroid gland	UBERON:0002046	75.54	gold quality
pituitary gland	UBERON:0000007	75.38	gold quality
right adrenal gland cortex	UBERON:0035827	75.29	gold quality
right adrenal gland	UBERON:0001233	75.20	gold quality
right coronary artery	UBERON:0001625	75.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

108 targeting FBXW8, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1827	99.63	68.57	3265

Literature-anchored findings (GeneRIF, showing 11)

• FBXW8 plays an essential role in cancer cell proliferation through proteolysis of cyclin D1. It may present new opportunities to develop therapies targeting destruction of cyclin D1 or its regulator E3 ligase selectively. (PMID:17205132)
• FBXW8-CUL7 complex plays a significant role in growth control (PMID:17998335)
• Fbxw8 plays an essential role in the proliferation of human trophoblast cells, especially JEG-3 cells. (PMID:20878477)
• Dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in intrauterine growth restriction. (PMID:22524683)
• Growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8. (PMID:23029530)
• 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)
• findings will shed light the role to mechanism of miR-218 in regulating JEG-3 cells proliferation via miR-218/Fbxw8 axis, and miR-218 may serve as a novel potential therapeutic target in human choriocarcinoma in the future (PMID:24973709)
• FBXW8 and PARK2 are sequestrated into insolubility by ATXN2 PolyQ expansions, but only FBXW8 expression is dysregulated (PMID:25790475)
• Frameshift mutation FBXW8 c.1312_1313delGT was considered functionally relevant and was investigated for its potential association with breast cancer risk through subsequent genotyping in two hospital-based breast cancer case-control series from Belarus and Germany, respectively, comprising a total of 2740 breast cancer cases and 2174 controls. (PMID:29310837)
• FBXW8 regulates G1 and S phases of cell cycle progression by restricting beta-TrCP1 function. (PMID:33742524)
• Genome-wide admixture and association analysis identifies African ancestry-specific risk loci of eosinophilic esophagitis in African Americans. (PMID:36400179)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxw8	ENSDARG00000079089
mus_musculus	Fbxw8	ENSMUSG00000032867
rattus_norvegicus	Fbxw8	ENSRNOG00000001126

Paralogs (14): WDR54 (ENSG00000005448), FBXW11 (ENSG00000072803), FBXW7 (ENSG00000109670), TRAF7 (ENSG00000131653), FBXW9 (ENSG00000132004), FBXO36 (ENSG00000153832), WDR64 (ENSG00000162843), FBXW12 (ENSG00000164049), BTRC (ENSG00000166167), WDR49 (ENSG00000174776), PAAF1 (ENSG00000175575), WDR86 (ENSG00000187260), FBXO16 (ENSG00000214050), EFCAB8 (ENSG00000215529)

Protein

Protein identifiers

F-box/WD repeat-containing protein 8 — Q8N3Y1 (reviewed: Q8N3Y1)

Alternative names: F-box and WD-40 domain-containing protein 8, F-box only protein 29

All UniProt accessions (2): A0A499FIY5, Q8N3Y1

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the Cul7-RING(FBXW8) ubiquitin ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The Cul7-RING(FBXW8) complex mediates ubiquitination and consequent degradation of GORASP1, acting as a component of the ubiquitin ligase pathway that 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. The Cul7-RING(FBXW8) complex also mediates ubiquitination of phosphorylated cyclin-D1 (CCND1). The Cul7-RING(FBXW8) complex is however not a major regulator of CCND1 stability during the G1/S transition. Associated component of the 3M complex, suggesting that it mediates some of 3M complex functions.

Subunit / interactions. Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8; within the complex interacts with CUL7 and SKP1. Interacts with GLMN isoform 1. Interacts with OBSL1, CUL1, CUL2, CCT6B, PFDN5, CCT2, CCT3, CCT6A, CCT7, VBP1, CCDC8, ARF1, TRIP13, PDCD5 and GORASP1. Interacts with MAP4K1/HPK1 (when autophosphorylated). Associated component of the 3M complex. Interacts with POUF51 (when phosphorylated on ‘Ser-355’).

Subcellular location. Cytoplasm. Perinuclear region. Golgi apparatus.

Post-translational modifications. Phosphorylation at Ser-85 by mTORC2 promotes FBXW8 stabilization, allowing its translocation to the cytosol in response to insulin.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N3Y1-1	1	yes
Q8N3Y1-2	2

RefSeq proteins (2): NP_036306, NP_699179* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR001810	F-box_dom	Domain
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR050505	WDR55/POC1	Family

Pfam: PF12937

UniProt features (77 total): strand 37, repeat 8, helix 8, turn 7, sequence variant 4, sequence conflict 4, modified residue 3, compositionally biased region 2, chain 1, domain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7Z8B	ELECTRON MICROSCOPY	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N3Y1-F1	77.10	0.49

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 (3): 1, 83, 85

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 201 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, 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_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (13): ubiquitin-dependent protein catabolic process (GO:0006511), Golgi organization (GO:0007030), cell population proliferation (GO:0008283), protein ubiquitination (GO:0016567), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of insulin receptor signaling pathway (GO:0046627), positive regulation of dendrite morphogenesis (GO:0050775), cilium assembly (GO:0060271), labyrinthine layer blood vessel development (GO:0060716), insulin receptor signaling pathway (GO:0008286), positive regulation of translation (GO:0045727), negative regulation of ubiquitin-dependent protein catabolic process (GO:2000059)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), centriole (GO:0005814), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), Cul7-RING ubiquitin ligase complex (GO:0031467), ciliary basal body (GO:0036064), perinuclear region of cytoplasm (GO:0048471), 3M complex (GO:1990393)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
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
ubiquitin-dependent protein catabolic process	2
microtubule organizing center	2
cullin-RING ubiquitin ligase complex	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
organelle organization	1
endomembrane system organization	1
cellular process	1
protein modification by small protein conjugation	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	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
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
embryonic organ development	1
placenta blood vessel development	1
labyrinthine layer development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
translation	1
regulation of translation	1

Protein interactions and networks

STRING

1216 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXW8	CUL7	Q14999	999
FBXW8	SKP1	P34991	997
FBXW8	RBX1	P62877	996
FBXW8	CUL1	Q13616	909
FBXW8	GLMN	Q92990	903
FBXW8	SKP2	Q13309	845
FBXW8	OBSL1	O75147	820
FBXW8	FBXO4	Q9UKT5	776
FBXW8	DDB1	Q16531	753
FBXW8	UBA3	Q8TBC4	732
FBXW8	CUL9	Q8IWT3	724
FBXW8	A0A087WY85	A0A087WY85	626
FBXW8	BTRC	Q9Y297	607
FBXW8	CCNF	P41002	589
FBXW8	CUL4A	Q13619	577

IntAct

74 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
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
SKP1	FBXW8	psi-mi:“MI:0915”(physical association)	0.740
TP53	CSNK2A2	psi-mi:“MI:0914”(association)	0.730
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
PDCL3	PEX7	psi-mi:“MI:0914”(association)	0.640
CCT3	TXNDC9	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
CUL1	FBXO21	psi-mi:“MI:0914”(association)	0.600
MYC	FBXW8	psi-mi:“MI:0915”(physical association)	0.570
FBXW8	MYC	psi-mi:“MI:0915”(physical association)	0.570
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
CASQ2	PES1	psi-mi:“MI:0914”(association)	0.530
RBBP4	TNRC18	psi-mi:“MI:0914”(association)	0.530
ZFC3H1	HNRNPCL1	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
CCT7	PEX7	psi-mi:“MI:0914”(association)	0.530
SKP1	FBXW8	psi-mi:“MI:0915”(physical association)	0.400
TP53	MDM2	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
CCT3	C6orf11	psi-mi:“MI:0914”(association)	0.350

BioGRID (327): EP300 (Affinity Capture-Western), SKP1 (Affinity Capture-MS), TCP1 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS), CUL1 (Affinity Capture-Western), FBXW8 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS), SKP1 (Affinity Capture-Western), FBXW8 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS), FBXW8 (Affinity Capture-MS)

ESM2 similar proteins: A8XEN7, A9UZS7, B0WYR6, C5DTN0, G5EF68, O16023, O16519, O24467, O45487, O94527, P0DOC0, P53015, P90794, Q09309, Q09373, Q09392, Q09589, Q09786, Q10990, Q15291, Q17I16, Q22071, Q24338, Q24371, Q26458, Q40153, Q5TTP0, Q5ZMV9, Q6CRJ7, Q6NL34, Q75BS7, Q75E79, Q7ZX22, Q8BX09, Q8CFJ9, Q8CIE6, Q8ISM1, Q8N3Y1, Q8TBZ3, Q94BQ3

Diamond homologs: A1C7E4, A1CBP8, A1CUD6, A1DDL6, A1DHW6, A1DP19, A2QCU8, A2R3Z3, A3LNI7, A4RJV3, A5D7H2, A7EKM8, B0XM00, B0XTS1, B2VWG7, B6GZA1, B6Q4Z5, B6QC06, B6QC56, B8M0Q1, B8M7Q5, B8NGT5, C0S902, C1GB49, C5FP68, C5GVJ9, C5JD40, D1ZEM6, D4AM37, D4D8P3, L7N1X6, O43815, O55106, P0DL28, P39014, P58404, P58405, P70483, P87053, Q00659

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
FBXW8	“down-regulates quantity by destabilization”	CCND1	binding
FBXW8	“up-regulates activity”	“Cullin 7-RBX1-Skp1”	binding
FBXW8	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
FBXW8	“down-regulates quantity by destabilization”	IRS1	binding
mTORC2	“up-regulates quantity by stabilization”	FBXW8	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 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
Formation of tubulin folding intermediates by CCT/TriC	5	39.2×	2e-05
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	5	37.8×	2e-05
Chaperonin-mediated protein folding	5	27.8×	7e-05
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	5	27.8×	7e-05
Association of TriC/CCT with target proteins during biosynthesis	5	27.1×	7e-05
Protein folding	5	24.0×	1e-04
Regulation of TP53 Activity through Phosphorylation	6	13.1×	3e-04
Cilium Assembly	5	10.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to UV	5	21.1×	6e-04
protein stabilization	7	6.7×	7e-03
protein ubiquitination	10	5.9×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	7
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2912 predictions. Top by Δscore:

Variant	Effect	Δscore
12:116911352:CCTGG:C	donor_loss	1.0000
12:116911356:GT:G	donor_loss	1.0000
12:116911357:T:A	donor_loss	1.0000
12:116928017:CCTCA:C	acceptor_loss	1.0000
12:116928018:CTCAG:C	acceptor_loss	1.0000
12:116928019:TCA:T	acceptor_loss	1.0000
12:116928020:CA:C	acceptor_loss	1.0000
12:116928021:A:AG	acceptor_gain	1.0000
12:116928021:AGAA:A	acceptor_loss	1.0000
12:116928021:AGAAT:A	acceptor_gain	1.0000
12:116928022:G:A	acceptor_loss	1.0000
12:116928022:G:GA	acceptor_gain	1.0000
12:116928022:GA:G	acceptor_gain	1.0000
12:116928022:GAA:G	acceptor_gain	1.0000
12:116928022:GAAT:G	acceptor_gain	1.0000
12:116928022:GAATG:G	acceptor_gain	1.0000
12:116928123:CACAG:C	donor_loss	1.0000
12:116928124:ACAG:A	donor_loss	1.0000
12:116928125:CAGG:C	donor_loss	1.0000
12:116928126:AGGTA:A	donor_loss	1.0000
12:116928127:GG:G	donor_loss	1.0000
12:116928128:G:GA	donor_loss	1.0000
12:116928129:T:A	donor_loss	1.0000
12:116945360:TTAGG:T	acceptor_loss	1.0000
12:116945361:TAG:T	acceptor_loss	1.0000
12:116945362:A:AC	acceptor_loss	1.0000
12:116945363:GGT:G	acceptor_gain	1.0000
12:116945363:GGTGA:G	acceptor_gain	1.0000
12:116945526:A:T	donor_gain	1.0000
12:116964692:TCCA:T	acceptor_loss	1.0000

AlphaMissense

3911 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:116945376:T:A	W146R	0.999
12:116945376:T:C	W146R	0.999
12:116928084:T:A	I127K	0.997
12:116945367:A:C	S143R	0.997
12:116945369:C:A	S143R	0.997
12:116945369:C:G	S143R	0.997
12:116945378:G:C	W146C	0.997
12:116945378:G:T	W146C	0.997
12:117024245:T:A	V489D	0.997
12:117024247:A:C	S490R	0.997
12:117024249:T:A	S490R	0.997
12:117024249:T:G	S490R	0.997
12:116945406:T:A	W156R	0.996
12:116945406:T:C	W156R	0.996
12:116945388:G:C	A150P	0.995
12:116928084:T:G	I127R	0.994
12:116928087:T:C	F128S	0.994
12:116928119:T:C	C139R	0.994
12:116945389:C:A	A150E	0.994
12:116945469:T:A	W177R	0.994
12:116945469:T:C	W177R	0.994
12:116964722:T:A	W235R	0.993
12:116964722:T:C	W235R	0.993
12:116928096:T:C	L131P	0.992
12:116945377:G:C	W146S	0.992
12:116945395:A:T	D152V	0.992
12:116985220:T:A	W284R	0.992
12:116985220:T:C	W284R	0.992
12:117010431:A:C	S450R	0.992
12:117010433:T:A	S450R	0.992

dbSNP variants (sampled 300 via entrez): RS1000016569 (12:116991084 A>C), RS1000024428 (12:117000915 C>T), RS1000024647 (12:116991472 C>G), RS1000027236 (12:116947451 C>G), RS1000028194 (12:117030935 T>C), RS1000087458 (12:116945213 A>G), RS1000089126 (12:116990618 T>A), RS1000115043 (12:116997930 C>T), RS1000142752 (12:116947752 AAAG>A), RS1000192140 (12:116909885 T>A), RS1000195489 (12:116952630 C>T), RS1000208444 (12:116909638 A>C), RS1000229309 (12:116997611 G>A), RS1000249499 (12:116966219 G>T), RS1000258212 (12:117025695 C>G)

Disease associations

OMIM: gene MIM:609073 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001481_2	Brain structure	7.000000e-16
GCST006870_7	Hippocampal tail volume	2.000000e-19
GCST006871_6	Total hippocampal volume	2.000000e-35
GCST006886_1	Subiculum volume	1.000000e-17
GCST006887_1	Hippocampal subfield CA1 volume	7.000000e-28
GCST006888_3	Hippocampal subfield CA3 volume	2.000000e-15
GCST006889_2	Hippocampal subfield CA4 volume	2.000000e-24
GCST006890_1	Dentate gyrus granule cell layer volume	9.000000e-26
GCST006891_5	Dentate gyrus molecular layer volume	2.000000e-25
GCST006894_1	HATA volume	4.000000e-13
GCST008726_1	Marginal zone lymphoma or rheumatoid arthritis	5.000000e-09
GCST010703_5	Brain morphology (MOSTest)	4.000000e-32

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume
EFO:0009394	hippocampal CA1 volume
EFO:0009395	hippocampal CA3 volume
EFO:0009396	hippocampal CA4 volume
EFO:0009401	hippocampal amigdala transition area volume
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Particulate Matter	increases abundance, increases expression	2
GSK-J4	decreases expression	1
titanium dioxide	decreases methylation	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
perfluorooctane sulfonic acid	increases expression	1
monomethylarsonous acid	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Arsenicals	increases methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Methapyrilene	decreases methylation	1
Testosterone	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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