FBXO22

Summary

FBXO22 (F-box protein 22, HGNC:13593) is a protein-coding gene on chromosome 15q24.2, encoding F-box only protein 22 (Q8NEZ5). Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex that is implicated in the control of various cellular processes such as cell cycle control, transcriptional regulation, DNA damage repair, and apoptosis.

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 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 belongs to the Fbxs class and, as a transcriptional target of the tumor protein p53, is thought to be involved in degradation of specific proteins in response to p53 induction. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 26263 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 64 total — 4 pathogenic
• Phenotypes (HPO): 119
• Druggable target: yes
• MANE Select transcript: NM_147188

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13593
Approved symbol	FBXO22
Name	F-box protein 22
Location	15q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FBX22, FISTC1
Ensembl gene	ENSG00000167196
Ensembl biotype	protein_coding
OMIM	609096
Entrez	26263

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000308275, ENST00000453211, ENST00000561885, ENST00000564220, ENST00000565036, ENST00000565131, ENST00000569022, ENST00000569054, ENST00000569749, ENST00000929297, ENST00000929298

RefSeq mRNA: 2 — MANE Select: NM_147188 NM_012170, NM_147188

CCDS: CCDS10287, CCDS45310

Canonical transcript exons

ENST00000308275 — 7 exons

Exon	Start	End
ENSE00001212189	75932685	75942511
ENSE00002602189	75903878	75904103
ENSE00003462083	75914110	75914205
ENSE00003505629	75913203	75913290
ENSE00003552363	75904491	75904629
ENSE00003633908	75917230	75917394
ENSE00003785064	75929884	75930049

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 91.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.4072 / max 174.1737, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147836	21.3540	1812
147835	4.2199	1533
207594	0.8333	528

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	91.33	gold quality
stromal cell of endometrium	CL:0002255	89.66	gold quality
cortical plate	UBERON:0005343	89.29	gold quality
islet of Langerhans	UBERON:0000006	88.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.98	gold quality
ventricular zone	UBERON:0003053	87.92	gold quality
ganglionic eminence	UBERON:0004023	87.76	gold quality
right adrenal gland cortex	UBERON:0035827	86.47	gold quality
right adrenal gland	UBERON:0001233	86.38	gold quality
left adrenal gland	UBERON:0001234	85.81	gold quality
colonic epithelium	UBERON:0000397	85.76	gold quality
left adrenal gland cortex	UBERON:0035825	85.12	gold quality
calcaneal tendon	UBERON:0003701	85.09	gold quality
adrenal gland	UBERON:0002369	85.07	gold quality
prefrontal cortex	UBERON:0000451	85.00	gold quality
right lobe of liver	UBERON:0001114	84.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.74	gold quality
rectum	UBERON:0001052	84.64	gold quality
adrenal cortex	UBERON:0001235	84.52	gold quality
gall bladder	UBERON:0002110	84.21	gold quality
pancreas	UBERON:0001264	84.20	gold quality
sperm	CL:0000019	84.02	gold quality
body of pancreas	UBERON:0001150	83.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.71	gold quality
gastrocnemius	UBERON:0001388	83.70	gold quality
muscle of leg	UBERON:0001383	83.54	gold quality
mucosa of transverse colon	UBERON:0004991	83.45	gold quality
adrenal tissue	UBERON:0018303	83.44	gold quality
descending thoracic aorta	UBERON:0002345	82.75	gold quality
gingival epithelium	UBERON:0001949	82.69	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

153 targeting FBXO22, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
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-548AT-5P	99.96	70.83	2666

Literature-anchored findings (GeneRIF, showing 25)

• FBXO22 is a key regulator of histone methylation marks, namely, H3K9 and H3K36 methylation, through the regulation of KDM4A protein levels. (PMID:21768309)
• we determined that the phage-encoded GogB effector protein in Salmonella targets the host SCF E3 type ubiquitin ligase through an interaction with Skp1 and the human F-box only 22 (FBXO22) protein (PMID:22761574)
• FBXO22 protein is required for optimal synthesis of NMDA receptor coagonist D-serine by interacting with serine racemase, activating it, and preventing its targeting to membranes. (PMID:25336657)
• Authors demonstrate that F-box only protein 22 (FBXO22) interacts with and thereby destabilizes KLF4 via polyubiquitination. As a result, FBXO22 could promote HCC cells proliferation. (PMID:26087183)
• Results indicate that SCF(Fbxo22)-KDM4A is an E3 ubiquitin ligase that targets methylated p53 and regulates key senescent processes. (PMID:26868148)
• Data show that FBXO22 mediated the polyubiquitination and degradation of CD147 by interacting with CD147 intracellular domain (CD147-ICD). (PMID:28117675)
• FBXO22 has two roles in breast cancer: it promotes breast tumor cell proliferation but prevents epithelial-mesenchymal transition and metastasis (PMID:29945959)
• the level of Fbxo22 in tumor tissues defines a new subclass of ER-positive breast cancers for which SCFFbxo22-mediated KDM4B degradation in patients can be a therapeutic target for the next generation of SERMs. (PMID:30418174)
• This study uncovered a new mechanism by which FBXO22 functions as an oncogene in hepatocellular carcinoma pathogenesis and progression by mediating the ubiquitination and degradation of p21 (PMID:30808376)
• Knockdown of FBXO22 inhibits melanoma cell migration, invasion and angiogenesis via the HIF-1alpha/VEGF pathway. (PMID:30887251)
• SCF(FBXO22) targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis. (PMID:31138683)
• FBXO22 is highly expressed in human lung adenocarcinoma and high FBXO22 expression predicts significant poor prognosis. (PMID:31217475)
• Long noncoding RNA SNHG14 promotes osteosarcoma progression via miR-433-3p/FBXO22 axis. (PMID:31948764)
• FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. (PMID:32249768)
• TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis. (PMID:33706682)
• Global identification of phospho-dependent SCF substrates reveals a FBXO22 phosphodegron and an ERK-FBXO22-BAG3 axis in tumorigenesis. (PMID:34215846)
• The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage. (PMID:34795058)
• Fbxo22 inhibits metastasis in triple-negative breast cancer through ubiquitin modification of KDM5A and regulation of H3K4me3 demethylation. (PMID:36112263)
• Fbxo22 promotes cervical cancer progression via targeting p57(Kip2) for ubiquitination and degradation. (PMID:36127346)
• FBXO22 Accelerates Pancreatic Cancer Growth by Deactivation of the Hippo Pathway via Destabilizing LATS2. (PMID:36515852)
• FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia. (PMID:36774506)
• FBXO22 inhibits proliferation and metastasis of cervical cancer cells by mediating ubiquitination-dependent degradation of GAK. (PMID:37442264)
• ELK4 Promotes Cell Cycle Progression and Stem Cell-like Characteristics in HPV-associated Cervical Cancer by Regulating the FBXO22/PTEN Axis. (PMID:37519006)
• TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22. (PMID:38673728)
• E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting proteasome-dependent degradation of NSP5. (PMID:39223933)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo22	ENSDARG00000053505
mus_musculus	Fbxo22	ENSMUSG00000032309
rattus_norvegicus	Fbxo22	ENSRNOG00000022702

Protein

Protein identifiers

F-box only protein 22 — Q8NEZ5 (reviewed: Q8NEZ5)

Alternative names: F-box protein FBX22p44

All UniProt accessions (6): Q8NEZ5, H3BRE0, H3BTH6, H3BTR7, H3BUC1, H3BVA4

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex that is implicated in the control of various cellular processes such as cell cycle control, transcriptional regulation, DNA damage repair, and apoptosis. Promotes the proteasome-dependent degradation of key sarcomeric proteins, such as alpha-actinin (ACTN2) and filamin-C (FLNC), essential for maintenance of normal contractile function. Acts as a key regulator of histone methylation marks namely H3K9 and H3K36 methylation through the regulation of histone demethylase KDM4A protein levels. In complex with KDM4A, also regulates the abundance of TP53 by targeting methylated TP53 for degradation at the late senescent stage. Under oxidative stress, promotes the ubiquitination and degradation of BACH1. Mechanistically, reactive oxygen species (ROS) covalently modify cysteine residues on the bZIP domain of BACH1, leading to its release from chromatin and making it accessible to FBXO22. Upon amino acid depletion, mediates ‘Lys-27’-linked ubiquitination of MTOR and thereby inhibits substrate recruitment to mTORC1. Also inhibits SARS-CoV-2 replication by inducing NSP5 degradation.

Subunit / interactions. Directly interacts with SKP1 and CUL1. Interacts (via C-terminal) with KDM4A. Interacts with TP53. Interacts with MTOR; this interaction promotes ’lys-27’-linked ubiquitination of MTOR. (Microbial infection) Interacts with SARS_COV-2 protein NSP5; this interaction attenuates NSP5-mediated inhibition of innate immunity.

Subcellular location. Cytoplasm. Nucleus. Myofibril. Sarcomere. Z line.

Tissue specificity. Predominantly expressed in liver, also enriched in cardiac muscle.

Post-translational modifications. Phosphorylated by EIF2AK4 at Thr-127 causes cytoplasmic retention of FBXO22.

Disease relevance. Tayoun-Maawali syndrome (TYMAS) [MIM:621184] An autosomal recessive pleiotropic syndrome characterized by multiple abnormalities encompassing early growth restriction, neurodevelopmental delay, and craniofacial, cardiovascular, gastrointestinal, urinary and endocrine anomalies. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NEZ5-1	1	yes
Q8NEZ5-2	2
Q8NEZ5-3	3

RefSeq proteins (2): NP_036302, NP_671717* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR019494	FIST_C	Domain
IPR036047	F-box-like_dom_sf	Homologous_superfamily

Pfam: PF00646, PF10442

UniProt features (46 total): strand 20, helix 11, modified residue 4, splice variant 3, sequence conflict 2, turn 2, chain 1, domain 1, mutagenesis site 1, sequence variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8S7D	ELECTRON MICROSCOPY	3.2
8S7E	ELECTRON MICROSCOPY	3.4
8UA3	ELECTRON MICROSCOPY	3.8
8UA6	ELECTRON MICROSCOPY	3.9
29HG	ELECTRON MICROSCOPY	4
29HH	ELECTRON MICROSCOPY	4.2
29HI	ELECTRON MICROSCOPY	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEZ5-F1	86.35	0.65

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 (4): 1, 127, 128, 194

Mutagenesis-validated functional residues (1):

Position	Phenotype
127	loss of eif2ak4-induced cytoplasmic retention of fbxo22.

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: 216 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, TTTGTAG_MIR520D, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, CHANDRAN_METASTASIS_DN, GOBP_NUCLEAR_TRANSPORT, WEI_MYCN_TARGETS_WITH_E_BOX

GO Biological Process (10): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), nucleocytoplasmic transport (GO:0006913), cellular response to starvation (GO:0009267), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), protein modification process (GO:0036211), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of skeletal muscle fiber development (GO:0048742), regulation of myotube differentiation (GO:0010830), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060)

GO Molecular Function (2): ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), Z disc (GO:0030018), cytoplasm (GO:0005737)

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
protein ubiquitination	2
ubiquitin-dependent protein catabolic process	2
modification-dependent protein catabolic process	1
nuclear transport	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	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
protein metabolic process	1
macromolecule modification	1
proteasomal protein catabolic process	1
regulation of myotube differentiation	1
skeletal muscle fiber development	1
regulation of cell development	1
myotube differentiation	1
regulation of striated muscle cell differentiation	1
positive regulation of protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
ubiquitin-like protein transferase activity	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
I band	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

742 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO22	SKP1	P34991	739
FBXO22	CUL1	Q13616	734
FBXO22	KDM4A	O75164	657
FBXO22	FBXL3	Q9UKT7	491
FBXO22	FBXL13	Q8NEE6	490
FBXO22	KLHL3	Q9UH77	465
FBXO22	FBXO34	Q9NWN3	435
FBXO22	FBXO21	O94952	419
FBXO22	FBXO45	P0C2W1	413
FBXO22	FBXO4	Q9UKT5	412
FBXO22	UBE2Q2	Q8WVN8	406
FBXO22	BACH1	O14867	385
FBXO22	FBXO11	Q86XK2	377
FBXO22	FBXL14	Q8N1E6	373
FBXO22	FBXO28	Q9NVF7	373

IntAct

56 interactions, top by confidence:

A	B	Type	Score
BACH1	MAFG	psi-mi:“MI:0914”(association)	0.870
SKP1	FBXO22	psi-mi:“MI:0915”(physical association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
CUL1	FBXO21	psi-mi:“MI:0914”(association)	0.600
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
FBXO22	CUL1	psi-mi:“MI:0915”(physical association)	0.500
CUL1	FBXO22	psi-mi:“MI:0915”(physical association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
FBXO22	E2	psi-mi:“MI:0915”(physical association)	0.370
FBXO22	NCOR2	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
COPS5		psi-mi:“MI:0914”(association)	0.350
COPS6		psi-mi:“MI:0914”(association)	0.350
pipB2	PSMD12	psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350
TTC9C	PLD2	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
BACH1	ENC1	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
GSDME	DDX39A	psi-mi:“MI:0914”(association)	0.350

BioGRID (640): FBXO22 (Affinity Capture-MS), FBXO22 (Reconstituted Complex), FBXO22 (Affinity Capture-Western), SKP1 (Affinity Capture-Western), FBXO22 (Proximity Label-MS), SKP1 (Affinity Capture-MS), NCOR2 (Affinity Capture-MS), FBXO22 (Affinity Capture-MS), FBXO22 (Affinity Capture-Western), KLF4 (Affinity Capture-Western), SKP1 (Affinity Capture-Western), FBXO22 (Affinity Capture-MS), FBXO22 (Affinity Capture-RNA), FBXO22 (Affinity Capture-MS), FBXO22 (Affinity Capture-MS)

ESM2 similar proteins: A2RT62, A4IIK1, B3FL73, F4I9T0, I1SSI5, I1SSI6, O22161, O22243, O74991, P21541, Q09299, Q09562, Q0DKP3, Q1EHT7, Q1L8H0, Q2R3K5, Q32LM4, Q38SD2, Q3UHC2, Q3ZBA7, Q570C0, Q5MJ12, Q5NBU5, Q5RE08, Q66H10, Q75A03, Q7KLI1, Q7XVM8, Q8BFZ4, Q8C4V4, Q8N4B4, Q8NEZ5, Q8RWQ8, Q8VYT5, Q8W104, Q96ME1, Q9FJ32, Q9FJ57, Q9LPW7, Q9LTX2

Diamond homologs: Q5RE08, Q78JE5, Q8NEZ5

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
FBXO22	“down-regulates quantity”	BACH1	ubiquitination
heme	“up-regulates activity”	FBXO22	“chemical activation”
FBXO22	“down-regulates quantity by destabilization”	BSG	binding
FBXO22	up-regulates	“Cullin 1-RBX1-Skp1”	binding
FBXO22	“down-regulates quantity by destabilization”	MDM2	ubiquitination
FBXO22	“down-regulates quantity by destabilization”	KDM4A	ubiquitination
FBXO22	“down-regulates quantity by destabilization”	KLF4	ubiquitination
FBXO22	“down-regulates quantity by destabilization”	SNAI1	ubiquitination
FBXO22	“down-regulates quantity by destabilization”	TP53	ubiquitination
FBXO22	“down-regulates quantity by destabilization”	BSG	ubiquitination
FBXO22	“down-regulates quantity by destabilization”	BAG3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	5	30.5×	2e-04
Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	5	26.1×	3e-04
KEAP1-NFE2L2 pathway	5	15.4×	9e-04
Neddylation	7	8.5×	9e-04
Antigen processing: Ubiquitination & Proteasome degradation	6	5.7×	8e-03
Cellular responses to stress	6	5.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	47
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1301814	NM_147188.3(FBXO22):c.159_162del (p.Arg53fs)	Pathogenic
3893215	NM_147188.3(FBXO22):c.8_36del (p.Pro3fs)	Pathogenic
3893216	NM_147188.3(FBXO22):c.719_722del (p.Val240fs)	Pathogenic
3893217	NM_147188.3(FBXO22):c.663_666delinsG (p.Val222del)	Pathogenic

SpliceAI

1595 predictions. Top by Δscore:

Variant	Effect	Δscore
15:75904030:T:G	donor_gain	1.0000
15:75904110:A:T	donor_gain	1.0000
15:75913201:A:AG	acceptor_gain	1.0000
15:75913202:G:GG	acceptor_gain	1.0000
15:75913202:GA:G	acceptor_gain	1.0000
15:75913202:GAAT:G	acceptor_gain	1.0000
15:75917228:A:AG	acceptor_gain	1.0000
15:75917229:G:GG	acceptor_gain	1.0000
15:75917229:GT:G	acceptor_gain	1.0000
15:75917390:AGTAG:A	donor_loss	1.0000
15:75917391:GTAG:G	donor_gain	1.0000
15:75917392:TAGG:T	donor_loss	1.0000
15:75917395:GT:G	donor_loss	1.0000
15:75917396:T:G	donor_loss	1.0000
15:75929880:GCA:G	acceptor_loss	1.0000
15:75929882:A:AG	acceptor_gain	1.0000
15:75929883:G:GC	acceptor_gain	1.0000
15:75929883:GGT:G	acceptor_gain	1.0000
15:75929883:GGTC:G	acceptor_gain	1.0000
15:75930045:GAAAA:G	donor_gain	1.0000
15:75930047:AAAGT:A	donor_loss	1.0000
15:75930048:AA:A	donor_gain	1.0000
15:75930049:AGT:A	donor_loss	1.0000
15:75930050:G:GG	donor_gain	1.0000
15:75930050:GT:G	donor_loss	1.0000
15:75930051:T:G	donor_loss	1.0000
15:75904100:CCTG:C	donor_loss	0.9900
15:75904101:CTG:C	donor_loss	0.9900
15:75904102:TGG:T	donor_loss	0.9900
15:75904104:GTGA:G	donor_loss	0.9900

AlphaMissense

2637 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:75932877:G:C	R329S	0.997
15:75932877:G:T	R329S	0.997
15:75932957:G:A	G356D	0.996
15:75904504:T:A	W52R	0.995
15:75904504:T:C	W52R	0.995
15:75913228:T:A	V102D	0.995
15:75932866:T:C	C326R	0.995
15:75932876:G:C	R329T	0.995
15:75932876:G:T	R329M	0.994
15:75932956:G:C	G356R	0.994
15:75932962:T:C	F358L	0.994
15:75932964:T:A	F358L	0.994
15:75932964:T:G	F358L	0.994
15:75932966:G:A	G359E	0.994
15:75932981:G:A	G364E	0.994
15:75930010:G:A	G252E	0.993
15:75932723:T:C	L278P	0.993
15:75932852:G:A	G321D	0.993
15:75930013:G:A	G253D	0.992
15:75932867:G:A	C326Y	0.992
15:75932868:C:G	C326W	0.992
15:75932975:A:T	E362V	0.992
15:75929914:T:A	V220D	0.991
15:75932990:G:C	R367P	0.991
15:75933077:T:C	L396P	0.991
15:75904506:G:C	W52C	0.990
15:75904506:G:T	W52C	0.990
15:75932720:G:A	G277E	0.990
15:75932980:G:A	G364R	0.990
15:75932980:G:C	G364R	0.990

dbSNP variants (sampled 300 via entrez): RS1000167999 (15:75916678 T>A), RS1000223241 (15:75924539 G>A), RS1000224456 (15:75907112 T>C), RS1000277525 (15:75937137 CAT>C), RS1000362232 (15:75909473 G>A), RS1000362769 (15:75922410 G>T), RS1000557232 (15:75922748 A>G), RS1000629539 (15:75937476 T>C,G), RS1000700686 (15:75907843 T>C), RS1000731395 (15:75907560 T>C), RS1000957303 (15:75936853 G>A,C), RS1000966550 (15:75924611 C>T), RS1001072103 (15:75931989 G>A), RS1001139690 (15:75930223 G>A,C,T), RS1001185171 (15:75908549 C>T)

Disease associations

OMIM: gene MIM:609096 | disease phenotypes: MIM:621184

GenCC curated gene-disease

Mondo (2): neurodevelopmental disorder (MONDO:0700092), Tayoun-Maawali syndrome (MONDO:0976286)

Orphanet (0):

HPO phenotypes

119 total (30 of 119 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000083	Renal insufficiency
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000103	Polyuria
HP:0000104	Renal agenesis
HP:0000107	Renal cyst
HP:0000189	Narrow palate
HP:0000212	Gingival overgrowth
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000297	Facial hypotonia
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000414	Bulbous nose
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000479	Abnormal retinal morphology
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000639	Nystagmus
HP:0000678	Dental crowding

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002828_24	Urate levels in obese individuals	8.000000e-06
GCST005985_43	Creatinine levels	1.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724687 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, increases expression, increases methylation	4
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Cisplatin	affects expression, increases expression	2
chloroacetaldehyde	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
deoxynivalenol	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
potassium bromate	increases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	decreases expression	1
beta-methylcholine	affects expression	1
adefovir dipivoxil	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Cidofovir	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Dactinomycin	affects cotreatment, increases expression	1
Clodronic Acid	increases expression	1
Doxorubicin	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Folic Acid	decreases expression	1
Formaldehyde	increases expression	1
Ifosfamide	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697395	Binding	Inhibition of FBXO22 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice