KLHL22

Summary

KLHL22 (kelch like family member 22, HGNC:25888) is a protein-coding gene on chromosome 22q11.21, encoding Kelch-like protein 22 (Q53GT1). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for chromosome alignment and localization of PLK1 at kinetochores.

Enables 14-3-3 protein binding activity and ubiquitin-like ligase-substrate adaptor activity. Involved in several processes, including cellular response to L-leucine; mitotic spindle assembly checkpoint signaling; and negative regulation of metabolic process. Located in several cellular components, including intercellular bridge; lysosome; and microtubule cytoskeleton. Part of Cul3-RING ubiquitin ligase complex.

Source: NCBI Gene 84861 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 80 total — 4 pathogenic
• MANE Select transcript: NM_032775

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25888
Approved symbol	KLHL22
Name	kelch like family member 22
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14360, KELCHL
Ensembl gene	ENSG00000099910
Ensembl biotype	protein_coding
OMIM	618020
Entrez	84861

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 24 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000328879, ENST00000423364, ENST00000431430, ENST00000443285, ENST00000444967, ENST00000451553, ENST00000458248, ENST00000470335, ENST00000479601, ENST00000487090, ENST00000490556, ENST00000494929, ENST00000871932, ENST00000871933, ENST00000871934, ENST00000871935, ENST00000871936, ENST00000871937, ENST00000871938, ENST00000871939, ENST00000871940, ENST00000912749, ENST00000912750, ENST00000912751, ENST00000957182, ENST00000957183, ENST00000957184, ENST00000957185, ENST00000957186

RefSeq mRNA: 1 — MANE Select: NM_032775 NM_032775

CCDS: CCDS13780

Canonical transcript exons

ENST00000328879 — 7 exons

Exon	Start	End
ENSE00001138240	20446443	20446676
ENSE00001293721	20441519	20442438
ENSE00001731680	20495760	20495795
ENSE00003469926	20471350	20471515
ENSE00003565502	20464858	20465576
ENSE00003616753	20488985	20489244
ENSE00003667948	20457808	20458000

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 92.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5386 / max 54.1666, expressed in 1754 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193200	6.2761	1723
193201	1.2625	924

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	92.58	gold quality
cerebellar hemisphere	UBERON:0002245	92.30	gold quality
cerebellar cortex	UBERON:0002129	92.24	gold quality
cerebellum	UBERON:0002037	90.77	gold quality
right frontal lobe	UBERON:0002810	90.18	gold quality
cortical plate	UBERON:0005343	89.72	gold quality
anterior cingulate cortex	UBERON:0009835	89.25	gold quality
cingulate cortex	UBERON:0003027	89.18	gold quality
granulocyte	CL:0000094	89.07	gold quality
stromal cell of endometrium	CL:0002255	88.94	gold quality
right ovary	UBERON:0002118	88.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.75	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.61	gold quality
prefrontal cortex	UBERON:0000451	88.50	gold quality
right lobe of thyroid gland	UBERON:0001119	88.12	gold quality
body of uterus	UBERON:0009853	88.04	gold quality
left ovary	UBERON:0002119	88.03	gold quality
endocervix	UBERON:0000458	87.97	gold quality
smooth muscle tissue	UBERON:0001135	87.91	gold quality
left lobe of thyroid gland	UBERON:0001120	87.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.78	gold quality
gastrocnemius	UBERON:0001388	87.74	gold quality
left uterine tube	UBERON:0001303	87.73	gold quality
muscle of leg	UBERON:0001383	87.70	gold quality
adenohypophysis	UBERON:0002196	87.70	gold quality
nucleus accumbens	UBERON:0001882	87.67	gold quality
pituitary gland	UBERON:0000007	87.26	gold quality
caudate nucleus	UBERON:0001873	87.16	gold quality
thyroid gland	UBERON:0002046	87.15	gold quality
ganglionic eminence	UBERON:0004023	87.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting KLHL22, 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-642A-5P	99.51	65.10	1152
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-2276-5P	96.27	65.85	937
HSA-MIR-6775-3P	95.76	65.91	982

Literature-anchored findings (GeneRIF, showing 4)

• CUL3/KLHL22 may contact two distinct motifs within PLK1 protein, consistent with the bivalent mode of substrate targeting. (PMID:24067371)
• KLHL22 plays a conserved role to mediate the activation of mTORC1 and downstream events; depletion of KLHL22 in breast cancer cells suppresses tumour growth in nude mice; therefore, pharmacological interventions targeting KLHL22 may have therapeutic potential for the treatment of breast cancer and age-related diseases (PMID:29769719)
• KLHL22 promotes malignant melanoma growth in vitro and in vivo by activating the PI3K/Akt/mTOR signaling pathway. (PMID:32484697)
• KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression. (PMID:33109719)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl22	ENSDARG00000088807
mus_musculus	Klhl22	ENSMUSG00000022750
rattus_norvegicus	Klhl22	ENSRNOG00000001878

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 22 — Q53GT1 (reviewed: Q53GT1)

All UniProt accessions (7): Q53GT1, C9J191, C9J2T1, C9J5F8, C9JHG1, C9JLE9, C9JRG9

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for chromosome alignment and localization of PLK1 at kinetochores. The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation. Monoubiquitination of PLK1 does not lead to PLK1 degradation. The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated ‘Lys-48’ polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway. It is therefore an amino acid-dependent activator within the amino acid-sensing branch of the TORC1 pathway, indirectly regulating different cellular processes including cell growth and autophagy.

Subunit / interactions. Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1. Interacts with PLK1. Interacts with DEPDC5 (via DEP domain); the interaction depends on amino acid availability. Interacts with YWHAE; required for the nuclear localization of KLHL22 upon amino acid starvation.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle. Nucleus. Lysosome.

Disease relevance. Defects in KLHL22 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Potential oncogene that is up-regulated in breast cancer cells and promotes tumor growth.

Isoforms (2)

UniProt ID	Names	Canonical?
Q53GT1-1	1	yes
Q53GT1-3	2

RefSeq proteins (1): NP_116164* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030575	KLHL22_BACK	Domain

Pfam: PF00651, PF01344, PF07707, PF24681

UniProt features (65 total): helix 20, strand 14, turn 11, repeat 6, modified residue 5, initiator methionine 1, chain 1, compositionally biased region 1, splice variant 1, sequence variant 1, mutagenesis site 1, sequence conflict 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8W4J	ELECTRON MICROSCOPY	3.06
8KHP	ELECTRON MICROSCOPY	3.67
8K8T	ELECTRON MICROSCOPY	3.8
8K9I	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53GT1-F1	89.69	0.83

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 (5): 2, 463, 466, 475, 605

Mutagenesis-validated functional residues (1):

Position	Phenotype
18	loss of interaction with ywhae. loss of nuclear localization upon amino acid starvation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 259 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_RESPONSE_TO_ACID_CHEMICAL, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP

GO Biological Process (21): mitotic sister chromatid segregation (GO:0000070), positive regulation of T cell mediated immune response to tumor cell (GO:0002842), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), mitotic spindle assembly checkpoint signaling (GO:0007094), negative regulation of autophagy (GO:0010507), positive regulation of cell growth (GO:0030307), negative regulation of type I interferon production (GO:0032480), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of T cell activation (GO:0050870), cell division (GO:0051301), cellular response to amino acid stimulus (GO:0071230), cellular response to L-leucine (GO:0071233), positive regulation of TORC1 signaling (GO:1904263), negative regulation of T cell mediated immune response to tumor cell (GO:0002841), protein ubiquitination (GO:0016567), cellular response to nutrient levels (GO:0031669), positive regulation of type I interferon production (GO:0032481), cellular response to amino acid starvation (GO:0034198), negative regulation of T cell activation (GO:0050868), negative regulation of TORC1 signaling (GO:1904262)

GO Molecular Function (3): 14-3-3 protein binding (GO:0071889), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (12): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosome (GO:0005764), centrosome (GO:0005813), polar microtubule (GO:0005827), cytosol (GO:0005829), microtubule cytoskeleton (GO:0015630), Cul3-RING ubiquitin ligase complex (GO:0031463), intercellular bridge (GO:0045171), mitotic spindle (GO:0072686), spindle (GO:0005819), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
T cell mediated immune response to tumor cell	2
regulation of T cell mediated immune response to tumor cell	2
protein ubiquitination	2
regulation of type I interferon production	2
type I interferon production	2
T cell activation	2
regulation of T cell activation	2
intracellular membraneless organelle	2
sister chromatid segregation	1
mitotic nuclear division	1
mitotic cell cycle process	1
positive regulation of T cell mediated immunity	1
positive regulation of immune response to tumor cell	1
modification-dependent protein catabolic process	1
mitotic cell cycle	1
negative regulation of mitotic metaphase/anaphase transition	1
spindle assembly checkpoint signaling	1
mitotic spindle checkpoint signaling	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
negative regulation of cytokine production	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
positive regulation of lymphocyte activation	1
positive regulation of leukocyte cell-cell adhesion	1
cellular process	1
response to amino acid	1
cellular response to acid chemical	1
response to L-leucine	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
positive regulation of TOR signaling	1
TORC1 signaling	1

Protein interactions and networks

STRING

1060 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL22	CUL3	Q13618	728
KLHL22	PLK1	P53350	616
KLHL22	RBX1	P62877	574
KLHL22	RNF152	Q8N8N0	572
KLHL22	THAP7	Q9BT49	517
KLHL22	AIFM3	Q96NN9	502
KLHL22	NPRL3	Q12980	483
KLHL22	ZNF74	Q16587	480
KLHL22	SCARF2	Q96GP6	480
KLHL22	DEPDC5	O75140	461
KLHL22	ZNRF1	Q8ND25	458
KLHL22	MED15	Q96RN5	457
KLHL22	SAMTOR	Q1RMZ1	451
KLHL22	SLC7A4	O43246	446
KLHL22	SNAP29	O95721	430

IntAct

168 interactions, top by confidence:

A	B	Type	Score
CUL3	KLHL22	psi-mi:“MI:0915”(physical association)	0.930
KLHL22	CUL3	psi-mi:“MI:0915”(physical association)	0.930
CUL3	KLHL12	psi-mi:“MI:0914”(association)	0.920
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
KLHL9	CUL3	psi-mi:“MI:0914”(association)	0.860
KLHL22	GLUD1	psi-mi:“MI:0914”(association)	0.840
KLHL22	GLUD1	psi-mi:“MI:0915”(physical association)	0.840
KLHL22	GLUD1	psi-mi:“MI:0407”(direct interaction)	0.840
CUL3	RBX1	psi-mi:“MI:0915”(physical association)	0.820
RPP25	POP7	psi-mi:“MI:0914”(association)	0.810
EMC7	EMC8	psi-mi:“MI:0914”(association)	0.790
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
KLHL22	NUDCD3	psi-mi:“MI:0915”(physical association)	0.740
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
KLHL26	CUL3	psi-mi:“MI:0914”(association)	0.730
LYRM2	NDUFAB1	psi-mi:“MI:0914”(association)	0.730
EMC3	EMC8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (200): KLHL22 (Affinity Capture-MS), KLHL22 (Affinity Capture-MS), KLHL22 (Affinity Capture-Western), PLK1 (Biochemical Activity), KLHL22 (Affinity Capture-MS), GLUD2 (Affinity Capture-MS), SCARF2 (Affinity Capture-MS), LYRM4 (Affinity Capture-MS), METTL15 (Affinity Capture-MS), ATG4C (Affinity Capture-MS), KLHL22 (Affinity Capture-MS), SCAF8 (Affinity Capture-MS), NFS1 (Affinity Capture-MS), C7orf55 (Affinity Capture-MS), KLHL22 (Affinity Capture-MS)

ESM2 similar proteins: A2AAX3, A2AUC9, B3DIV9, D2HEW7, D3ZA50, D3ZZC3, E9QJ30, G3X9X1, O14682, O35709, O60662, Q08BL9, Q0D2A9, Q1LYM6, Q2TBA0, Q2WGJ6, Q3B7M1, Q4KLM4, Q53GT1, Q56A24, Q5EB39, Q5RCQ9, Q5RDY3, Q5RGB8, Q5U504, Q5U575, Q5ZJU2, Q66HD2, Q6DEL7, Q6DFF7, Q6GQU2, Q6NYM1, Q6Q7X9, Q6TFL4, Q6V595, Q8BRG6, Q8BWA5, Q8CA72, Q8IY47, Q8N4N3

Diamond homologs: A0JN76, A1YPR0, A6QQY2, B0WWP2, B1WBS3, B2RXF5, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, C9JR72, D2HEW7, D3ZZC3, E0CZ16, E9Q4F2, F1LZ52, F1MBP6, O14867, O15062, O43167, O88282, O88939, O93567, O94889, O95365, P97302, P97303, Q08CY1, Q0IJ29, Q0P4X6, Q13105, Q16RL8, Q1L8W0, Q2M0J9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
KLHL22	“down-regulates activity”	PLK1	binding
KLHL22	“up-regulates activity”	“Cullin 3-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 173 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
Neddylation	14	5.8×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein neddylation	6	27.4×	3e-05
proteasome-mediated ubiquitin-dependent protein catabolic process	16	5.4×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	67
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2571168	GRCh37/hg19 22q11.21(chr22:18893888-21481925)x1	Pathogenic
2580309	GRCh37/hg19 22q11.21(chr22:18893838-21416074)x3	Pathogenic
268073	GRCh37/hg19 22q11.21(chr22:18919579-21460595)x1	Pathogenic
548983	GRCh37/hg19 22q11.21(chr22:20733495-21463730)x1	Pathogenic

SpliceAI

2194 predictions. Top by Δscore:

Variant	Effect	Δscore
22:20446439:TCACC:T	donor_loss	1.0000
22:20446440:CA:C	donor_loss	1.0000
22:20446441:A:AC	donor_gain	1.0000
22:20446442:C:CC	donor_gain	1.0000
22:20446442:C:G	donor_loss	1.0000
22:20446674:CAC:C	acceptor_gain	1.0000
22:20446688:C:CT	acceptor_gain	1.0000
22:20446692:A:T	acceptor_gain	1.0000
22:20457801:T:TA	donor_gain	1.0000
22:20457802:CCTTA:C	donor_loss	1.0000
22:20457803:CTTAC:C	donor_loss	1.0000
22:20457804:TTACC:T	donor_loss	1.0000
22:20457805:TACCT:T	donor_loss	1.0000
22:20457806:A:AC	donor_gain	1.0000
22:20457806:A:C	donor_loss	1.0000
22:20457806:ACCT:A	donor_gain	1.0000
22:20457806:ACCTC:A	donor_gain	1.0000
22:20457807:C:A	donor_loss	1.0000
22:20457807:C:CC	donor_gain	1.0000
22:20457807:CCT:C	donor_gain	1.0000
22:20457807:CCTC:C	donor_gain	1.0000
22:20457807:CCTCC:C	donor_gain	1.0000
22:20457809:T:TA	donor_gain	1.0000
22:20457810:C:A	donor_gain	1.0000
22:20471511:TTCCT:T	acceptor_gain	1.0000
22:20471513:CCT:C	acceptor_gain	1.0000
22:20471514:CT:C	acceptor_gain	1.0000
22:20471514:CTC:C	acceptor_gain	1.0000
22:20471515:TCT:T	acceptor_gain	1.0000
22:20471516:C:CC	acceptor_gain	1.0000

AlphaMissense

4156 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:20442259:C:A	W573C	0.999
22:20442259:C:G	W573C	0.999
22:20442261:A:G	W573R	0.999
22:20442261:A:T	W573R	0.999
22:20442282:A:C	Y566D	0.999
22:20442408:A:G	W524R	0.999
22:20442408:A:T	W524R	0.999
22:20446483:C:T	G500D	0.999
22:20446486:C:T	G499E	0.999
22:20446487:C:A	G499W	0.999
22:20446529:A:G	W485R	0.999
22:20446529:A:T	W485R	0.999
22:20457835:C:A	W426C	0.999
22:20457835:C:G	W426C	0.999
22:20457837:A:G	W426R	0.999
22:20457837:A:T	W426R	0.999
22:20457893:C:G	R407P	0.999
22:20457978:A:G	W379R	0.999
22:20457978:A:T	W379R	0.999
22:20457999:A:C	Y372D	0.999
22:20464906:C:T	G355E	0.999
22:20464916:A:C	Y352D	0.999
22:20464986:C:A	W328C	0.999
22:20464986:C:G	W328C	0.999
22:20464988:A:G	W328R	0.999
22:20464988:A:T	W328R	0.999
22:20465553:G:C	C139W	0.999
22:20471363:G:T	A127D	0.999
22:20471364:C:G	A127P	0.999
22:20471372:A:G	L124P	0.999

dbSNP variants (sampled 300 via entrez): RS1000108991 (22:20480884 T>G), RS1000110972 (22:20444119 C>T), RS1000137524 (22:20441042 G>A), RS1000186142 (22:20481666 C>T), RS1000224527 (22:20449295 C>T), RS1000277071 (22:20449558 G>A), RS1000328287 (22:20493081 C>T), RS1000339965 (22:20459819 T>C), RS1000340273 (22:20486751 G>A), RS1000373963 (22:20494677 C>T), RS1000388915 (22:20494930 A>C,G), RS1000447260 (22:20453251 TTTC>T), RS1000458377 (22:20481052 C>A,T), RS1000538582 (22:20482506 C>T), RS1000609565 (22:20448105 A>C,G)

Disease associations

OMIM: gene MIM:618020 | disease phenotypes: MIM:192430, MIM:611867

GenCC curated gene-disease

Mondo (2): velocardiofacial syndrome (MONDO:0008644), chromosome 22q11.2 deletion syndrome, distal (MONDO:0012740)

Orphanet (2): Distal 22q11.2 microdeletion syndrome (Orphanet:261330), 22q11.2 deletion syndrome (Orphanet:567)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001854_11	Retinopathy in non-diabetics	6.000000e-06
GCST006482_26	Lung function (FEV1/FVC)	3.000000e-10
GCST006482_27	Lung function (FEV1/FVC)	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567511	Chromosome 22q11.2 Deletion Syndrome, Distal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, decreases expression	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Disulfiram	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00768820	PHASE4	RECRUITING	The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome
NCT05290493	PHASE2	COMPLETED	NB-001 in Children and Adolescents With 22q11 Deletion Syndrome
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT02070211	PHASE2/PHASE3	UNKNOWN	Indicated Prevention With Long-chain Polyunsaturated Omega-3 Fatty Acids in Patients With 22q11 Microdeletion Syndrome.
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00005102	Not specified	UNKNOWN	Immunologic Evaluation in Patients With DiGeorge Syndrome or Velocardiofacial Syndrome
NCT00105274	Not specified	COMPLETED	Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
NCT00917189	Not specified	COMPLETED	Computerized Cognitive Skills Training for Adolescents With Velocardiofacial Syndrome
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT05664412	Not specified	RECRUITING	Using Transcranial Alternating Current Stimulation to Improve Executive Function in 22q11.2 Deletion Syndrome
NCT05849441	Not specified	COMPLETED	Mindfulness Program for Adolescents With 22q11DS