CUL9

Summary

CUL9 (cullin 9, HGNC:15982) is a protein-coding gene on chromosome 6p21.1, encoding Cullin-9 (Q8IWT3). Core component of a Cul9-RING ubiquitin-protein ligase complex composed of CUL9 and RBX1.

Predicted to enable ubiquitin protein ligase activity. Involved in microtubule cytoskeleton organization; protein ubiquitination; and regulation of mitotic nuclear division. Located in cytosol. Part of cullin-RING ubiquitin ligase complex.

Source: NCBI Gene 23113 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 459 total
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_015089

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15982
Approved symbol	CUL9
Name	cullin 9
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	H7AP1, KIAA0708, PARC
Ensembl gene	ENSG00000112659
Ensembl biotype	protein_coding
OMIM	607489
Entrez	23113

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 13 retained_intron, 6 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000252050, ENST00000372647, ENST00000451399, ENST00000502719, ENST00000502937, ENST00000503766, ENST00000504485, ENST00000504647, ENST00000505172, ENST00000505405, ENST00000506830, ENST00000508656, ENST00000510282, ENST00000512408, ENST00000512423, ENST00000513904, ENST00000515344, ENST00000515773, ENST00000885096, ENST00000885097, ENST00000885098, ENST00000912223

RefSeq mRNA: 1 — MANE Select: NM_015089 NM_015089

CCDS: CCDS4890

Canonical transcript exons

ENST00000252050 — 41 exons

Exon	Start	End
ENSE00000850069	43196069	43196265
ENSE00000850070	43196645	43196862
ENSE00002051871	43182196	43182249
ENSE00003459617	43187713	43188118
ENSE00003469380	43204933	43205115
ENSE00003470317	43198609	43198855
ENSE00003471736	43187246	43187439
ENSE00003477421	43221158	43221321
ENSE00003477934	43203417	43203592
ENSE00003491879	43188523	43188715
ENSE00003491949	43186960	43187095
ENSE00003493949	43185456	43185610
ENSE00003496797	43213438	43213567
ENSE00003498337	43202716	43202821
ENSE00003499098	43220747	43220911
ENSE00003500324	43221685	43221778
ENSE00003514279	43224095	43224168
ENSE00003518754	43205263	43205423
ENSE00003519217	43220459	43220599
ENSE00003519731	43213713	43213912
ENSE00003520888	43199266	43199371
ENSE00003522015	43204748	43204857
ENSE00003527043	43193001	43193208
ENSE00003543281	43204360	43204539
ENSE00003548979	43222531	43222641
ENSE00003555020	43213149	43213294
ENSE00003556162	43216158	43216503
ENSE00003560698	43206007	43206235
ENSE00003564869	43184302	43184905
ENSE00003566754	43222779	43222896
ENSE00003569241	43222316	43222390
ENSE00003569644	43199929	43200156
ENSE00003571415	43224250	43224587
ENSE00003581192	43185955	43186455
ENSE00003582446	43223264	43223397
ENSE00003585593	43206321	43206510
ENSE00003593241	43203854	43203987
ENSE00003595624	43203109	43203204
ENSE00003597417	43200663	43200834
ENSE00003604678	43200436	43200526
ENSE00003648131	43215079	43215326

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 95.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.8455 / max 105.5080, expressed in 1686 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67883	5.4009	1665
67887	0.1636	49
67888	0.1216	67
67886	0.1092	40
67885	0.0429	16
67884	0.0074	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	95.67	gold quality
left testis	UBERON:0004533	95.62	gold quality
right frontal lobe	UBERON:0002810	95.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.06	gold quality
lower esophagus mucosa	UBERON:0035834	94.57	gold quality
adenohypophysis	UBERON:0002196	94.50	gold quality
cerebellar hemisphere	UBERON:0002245	94.43	gold quality
granulocyte	CL:0000094	94.33	gold quality
cerebellar cortex	UBERON:0002129	94.31	gold quality
right lobe of thyroid gland	UBERON:0001119	93.64	gold quality
skin of abdomen	UBERON:0001416	93.51	gold quality
skin of leg	UBERON:0001511	93.47	gold quality
putamen	UBERON:0001874	93.38	gold quality
spleen	UBERON:0002106	93.38	gold quality
pituitary gland	UBERON:0000007	93.37	gold quality
left lobe of thyroid gland	UBERON:0001120	93.28	gold quality
nucleus accumbens	UBERON:0001882	93.26	gold quality
cingulate cortex	UBERON:0003027	93.21	gold quality
testis	UBERON:0000473	93.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.14	gold quality
anterior cingulate cortex	UBERON:0009835	93.13	gold quality
metanephros cortex	UBERON:0010533	92.97	gold quality
caudate nucleus	UBERON:0001873	92.90	gold quality
amygdala	UBERON:0001876	92.71	gold quality
right uterine tube	UBERON:0001302	92.67	gold quality
cerebellum	UBERON:0002037	92.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.53	gold quality
sural nerve	UBERON:0015488	92.25	gold quality
thyroid gland	UBERON:0002046	92.20	gold quality
mucosa of transverse colon	UBERON:0004991	92.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting CUL9, 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-545-3P	99.95	70.74	2783
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-6818-5P	97.50	67.10	1167
HSA-MIR-6759-3P	96.94	68.31	823
HSA-MIR-769-5P	94.45	64.56	603

Literature-anchored findings (GeneRIF, showing 11)

• Parc, a Parkin-like ubiquitin ligase,is a critical regulator in controlling p53 subcellular cytoplasmic localization and subsequent function. (PMID:12526791)
• FUBP1 is an authentic substrate of Parkin that might play an important role in development of Parkinson disease pathology along with aminoacyl-tRNA synthetase interacting multifunctional protein type 2 (PMID:16672220)
• CPH domain interaction surface of p53 resides in the tetramerization domain and is formed by residues contributed by at least two subunits (PMID:17298945)
• PARC and CUL7 subcomplexes exhibit E3 ubiquitin ligase activity in vitro. (PMID:17332328)
• These studies suggest that PARC-interacting peptides are promising candidates for the enhancement of p53-dependent apoptosis in tumors with wt cytoplasmic p53. (PMID:18230339)
• the regulation of p53 subcellular localization and apoptosis by PARC as a contributing factor in CDDP resistance in OVCA cells and Ca(2+)/calpain in PARC post-translational processing and chemosensitivity. (PMID:22117079)
• PARC (also known as CUL9) was found to be the ubiquitin ligase responsible for the ubiquitination and proteasomal degradation of cytochrome c, thus promoting cell survival. (PMID:25028716)
• PARC-mediated ubiquitination and degradation of Cyt c is a strategy engaged by both neurons and cancer cells to prevent apoptosis during conditions of mitochondrial stress. (PMID:25028717)
• Results in U2OS cells demonstrate that the functions of CUL9 in regulating cell proliferation and maintaining genomic integrity are mainly mediated by p53, and that CUL9 is a critical p53 activator. (PMID:28481879)
• A proteomics approach for the identification of cullin-9 (CUL9) related signaling pathways in induced pluripotent stem cell models. (PMID:33705438)
• Noncanonical assembly, neddylation and chimeric cullin-RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex. (PMID:38605244)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cul9	ENSMUSG00000040327
rattus_norvegicus	Cul9	ENSRNOG00000018372

Paralogs (1): CUL7 (ENSG00000044090)

Protein

Protein identifiers

Cullin-9 — Q8IWT3 (reviewed: Q8IWT3)

Alternative names: UbcH7-associated protein 1, p53-associated parkin-like cytoplasmic protein

All UniProt accessions (4): E9PEZ1, Q8IWT3, H0Y8H9, H0YA00

UniProt curated annotations — full annotation on UniProt →

Function. Core component of a Cul9-RING ubiquitin-protein ligase complex composed of CUL9 and RBX1. The CUL9-RBX1 complex mediates ubiquitination and subsequent degradation of BIRC5 and is required to maintain microtubule dynamics and genome integrity. Acts downstream of the 3M complex, which inhibits the ubiquitination of BIRC5. The CUL9-RBX1 complex also mediates mono-ubiquitination of p53/TP53. Acts as a cytoplasmic anchor protein in p53/TP53-associated protein complex. Regulates the subcellular localization of p53/TP53 and its subsequent function. Ubiquitinates apurinic/apyrimidinic endodeoxyribonuclease APEX2. Ubiquitination by the CUL9-RBX1 complex is predominantly mediated by E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2D2.

Subunit / interactions. Component of the Cul9-RING complex consisting of CUL9 and RBX1; the CUL9-RBX1 complex is a heterododecamer composed of six CUL9 and six RBX1 protomers. Interacts (via C-terminal TRIAD/RBR supradomain) with E2 ubiquitin-conjugating enzyme UBE2L3. Interacts with CUL7; the interaction with the CUL7 component of the 3M complex leads to inhibition of CUL9 activity. The CUL7-CUL9 heterodimer seems to interact specifically with TP53, likely via the CPH domain. Forms a complex with p53/TP53 in the cytoplasm of unstressed cells. Interacts with UBCH7 and UBCH8.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitously expressed in all tissues with highest expression in testis brain and kidney.

Post-translational modifications. Autoubiquitinated by the CUL9-RBX1 complex at Lys-87. Neddylated. Neddylation is mediated by E1 enzyme UBA3-NAE1 complex and E2 enzyme UBE2F. Structural rearrangment of the C-terminal TRIAD/RBR supradomain may play a role in neddylation and deneddylation.

Domain organisation. The C-terminal TRIAD/RBR supradomain is essential for ubiquitination activity. The IBR domain is required for interaction with UBCH7 and UBCH8. The CPH and RING-type 1 domains are necessary for ubiquitination of TP53 by the CUL9-RBX1 complex. The DOC domain is necessary for ubiquitination of APEX2 by the CUL9-RBX1 complex.

Similarity. Belongs to the cullin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IWT3-1	1	yes
Q8IWT3-3	2

RefSeq proteins (1): NP_055904* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR002867	IBR_dom	Domain
IPR004939	APC_su10/DOC_dom	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR014722	Rib_uL2_dom2	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR016157	Cullin_CS	Conserved_site
IPR016158	Cullin_homology	Domain
IPR017907	Znf_RING_CS	Conserved_site
IPR019559	Cullin_neddylation_domain	Domain
IPR021097	CPH_domain	Domain
IPR036317	Cullin_homology_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR044066	TRIAD_supradom	Domain
IPR045093	Cullin	Family
IPR047560	Rcat_RBR_CUL9	Domain
IPR047561	BRcat_RBR_CUL9	Domain
IPR047562	RING-HC_RBR_CUL9	Domain
IPR055486	CUL7/CUL9_N	Domain
IPR056405	ARM_CUL7_CUL9	Domain
IPR059120	Cullin-like_AB	Domain

Pfam: PF01485, PF03256, PF11515, PF22191, PF23168, PF24742, PF26557

UniProt features (154 total): helix 55, binding site 25, strand 21, sequence conflict 10, compositionally biased region 8, turn 7, region of interest 6, mutagenesis site 5, zinc finger region 3, modified residue 3, domain 2, coiled-coil region 2, cross-link 2, sequence variant 2, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8RHZ	ELECTRON MICROSCOPY	3.37
8Q7H	ELECTRON MICROSCOPY	4.1
8Q7E	ELECTRON MICROSCOPY	4.4
2JUF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWT3-F1	67.64	0.03

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 (1): 2249

Ligand- & substrate-binding residues (25): 1363–1370; 2070; 2073; 2088; 2090; 2093; 2096; 2115; 2120; 2160; 2166; 2181 …

Post-translational modifications (5): 976, 1457, 2436, 87, 1881

Mutagenesis-validated functional residues (5):

Position	Phenotype
125	dimeric; disrupts the hexamerization of the cul9-rbx1 complex; when associated with a-152. monomeric; abolishes ubiquiti
152	dimeric; disrupts the hexamerization of the cul9-rbx1 complex; when associated with a-125. monomeric; abolishes ubiquiti
1650–1690	dimeric; disrupts the hexamerization of the cul9-rbx1 complex and abolishes ubiquitination of tp53 and apex2. monomeric;
1881	abolishes neddylation. abolishes ubiquitination of tp53 and apex2 by the cul9-rbx1 complex.
2249	abolishes ubiquitination of tp53 and apex2 by the cul9-rbx1 complex.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 130 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_REGULATION_OF_NUCLEAR_DIVISION, MODULE_255, SCHWAB_TARGETS_OF_BMYB_POLYMORPHIC_VARIANTS_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, MODULE_66, GOBP_ORGANELLE_FISSION, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MITOTIC_NUCLEAR_DIVISION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_MITOTIC_CELL_CYCLE, ACEVEDO_LIVER_CANCER_UP, MODULE_11, GOBP_REGULATION_OF_CELL_CYCLE_PROCESS

GO Biological Process (4): microtubule cytoskeleton organization (GO:0000226), ubiquitin-dependent protein catabolic process (GO:0006511), regulation of mitotic nuclear division (GO:0007088), protein ubiquitination (GO:0016567)

GO Molecular Function (9): ATP binding (GO:0005524), zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), ubiquitin protein ligase activity (GO:0061630), nucleotide binding (GO:0000166), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): cytosol (GO:0005829), cullin-RING ubiquitin ligase complex (GO:0031461), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoskeleton organization	1
microtubule-based process	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
regulation of mitotic cell cycle	1
regulation of cell cycle process	1
regulation of nuclear division	1
mitotic nuclear division	1
protein modification by small protein conjugation	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1242 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CUL9	ANAPC10	Q9UM13	865
CUL9	RBX1	P62877	823
CUL9	CUL5	Q93034	784
CUL9	CUL2	Q13617	772
CUL9	CUL3	Q13618	742
CUL9	FBXW8	Q8N3Y1	724
CUL9	TP53	P04637	714
CUL9	NEDD8	Q15843	712
CUL9	RNF7	Q9UBF6	615
CUL9	CUL4A	Q13619	613
CUL9	ANAPC7	Q9UJX3	587
CUL9	CUL4B	Q13620	574
CUL9	ANAPC11	Q9NYG5	536
CUL9	GLMN	Q92990	527
CUL9	CUL1	Q13616	512

IntAct

60 interactions, top by confidence:

A	B	Type	Score
TP53	MDM2	psi-mi:“MI:0914”(association)	1.000
TP53	MDM4	psi-mi:“MI:0914”(association)	0.970
TP53	CUL9	psi-mi:“MI:0915”(physical association)	0.920
CUL9	TP53	psi-mi:“MI:0914”(association)	0.920
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
TP53	CDKN1A	psi-mi:“MI:0914”(association)	0.820
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
GLMN	CUL2	psi-mi:“MI:0914”(association)	0.640
RAB6B	SBF1	psi-mi:“MI:0914”(association)	0.530
RAB6B	RAB6A	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
RNF7	SOCS7	psi-mi:“MI:0914”(association)	0.530
SRC	CUL9	psi-mi:“MI:0915”(physical association)	0.400
CUL9	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
CUL9	Klc1	psi-mi:“MI:0915”(physical association)	0.400
PLXNB3	CUL9	psi-mi:“MI:0915”(physical association)	0.370
TP53	MDM2	psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
SOX2	SEC16A	psi-mi:“MI:0914”(association)	0.350
TP53	DNAJA2	psi-mi:“MI:0914”(association)	0.350
MAP1LC3B		psi-mi:“MI:0914”(association)	0.350
TP53	SUPT5H	psi-mi:“MI:0914”(association)	0.350
TP53	DNM1L	psi-mi:“MI:0914”(association)	0.350
TP53	SAP18	psi-mi:“MI:0914”(association)	0.350
ZKSCAN8	ZNF320	psi-mi:“MI:0914”(association)	0.350

BioGRID (249): CUL9 (Affinity Capture-MS), CYCS (Affinity Capture-Western), CYCS (Biochemical Activity), UBE2G1 (Reconstituted Complex), CUL9 (Affinity Capture-MS), CUL9 (Affinity Capture-MS), CUL9 (Affinity Capture-MS), CUL9 (Affinity Capture-MS), CUL9 (Affinity Capture-MS), CUL9 (Reconstituted Complex), CUL9 (Affinity Capture-MS), CUL9 (Protein-RNA), CUL9 (Co-fractionation), CUL9 (Co-fractionation), VDAC3 (Co-fractionation)

ESM2 similar proteins: A1L3I3, A2AHC3, A7E2V4, A7E305, D3Z8E6, E9Q0S6, O70405, O75385, P0C0T2, P53995, Q13009, Q29RJ0, Q3UHH1, Q3UHU5, Q5DTT2, Q5T5Y3, Q5VWQ0, Q5ZHX5, Q60610, Q62233, Q6GQX6, Q6NZR2, Q6P0Q8, Q6P1R3, Q6P2E9, Q6ZPY7, Q6ZQF7, Q76I79, Q76LL6, Q76N89, Q7TNN8, Q80TB7, Q80TC6, Q80TT8, Q80VC9, Q80Y50, Q8C7B8, Q8CGB6, Q8IWT3, Q8WYL5

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

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NAE	“up-regulates activity”	CUL9	neddylation
Ub:E2	“up-regulates activity”	CUL9	ubiquitination
CUL9	“down-regulates quantity by destabilization”	FERMT2	ubiquitination
CUL9	“down-regulates quantity by destabilization”	FERMT1	ubiquitination
CUL9	“down-regulates quantity”	BIRC5	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 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	8	7.2×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	12	7.5×	3e-05
proteasome-mediated ubiquitin-dependent protein catabolic process	9	7.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	338
Likely benign	52
Benign	22

Top pathogenic / likely-pathogenic (0)

SpliceAI

7091 predictions. Top by Δscore:

Variant	Effect	Δscore
6:43187041:GA:G	donor_gain	1.0000
6:43188116:GTG:G	donor_gain	1.0000
6:43192996:GTCA:G	acceptor_loss	1.0000
6:43192999:A:AG	acceptor_gain	1.0000
6:43193000:G:GA	acceptor_gain	1.0000
6:43193000:GA:G	acceptor_gain	1.0000
6:43193000:GAGA:G	acceptor_gain	1.0000
6:43193205:GGCG:G	donor_gain	1.0000
6:43193206:GCG:G	donor_gain	1.0000
6:43193206:GCGG:G	donor_gain	1.0000
6:43193208:GGT:G	donor_loss	1.0000
6:43193209:G:GG	donor_gain	1.0000
6:43193210:T:A	donor_loss	1.0000
6:43196205:GCTC:G	donor_gain	1.0000
6:43198591:T:TA	acceptor_gain	1.0000
6:43198600:T:TA	acceptor_gain	1.0000
6:43199402:G:T	donor_gain	1.0000
6:43199902:A:G	acceptor_gain	1.0000
6:43200154:CAG:C	donor_loss	1.0000
6:43200155:AGGTG:A	donor_loss	1.0000
6:43200156:GG:G	donor_loss	1.0000
6:43200157:GT:G	donor_loss	1.0000
6:43200158:T:A	donor_loss	1.0000
6:43200374:T:TA	acceptor_gain	1.0000
6:43200375:G:A	acceptor_gain	1.0000
6:43200525:GG:G	donor_gain	1.0000
6:43200526:GG:G	donor_gain	1.0000
6:43200654:T:TA	acceptor_gain	1.0000
6:43200658:CCCA:C	acceptor_loss	1.0000
6:43200659:CCAG:C	acceptor_loss	1.0000

AlphaMissense

16413 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:43221275:T:A	C2236S	1.000
6:43221275:T:C	C2236R	1.000
6:43221276:G:C	C2236S	1.000
6:43221692:T:C	C2254R	1.000
6:43221693:G:A	C2254Y	1.000
6:43221694:T:G	C2254W	1.000
6:43221713:T:C	F2261L	1.000
6:43221715:C:A	F2261L	1.000
6:43221715:C:G	F2261L	1.000
6:43221716:T:C	C2262R	1.000
6:43221717:G:A	C2262Y	1.000
6:43221718:C:G	C2262W	1.000
6:43221719:T:A	W2263R	1.000
6:43221719:T:C	W2263R	1.000
6:43221721:G:C	W2263C	1.000
6:43221721:G:T	W2263C	1.000
6:43221725:T:C	C2265R	1.000
6:43221737:T:A	W2269R	1.000
6:43221737:T:C	W2269R	1.000
6:43221739:G:C	W2269C	1.000
6:43221739:G:T	W2269C	1.000
6:43221767:T:C	C2279R	1.000
6:43200767:T:A	W1194R	0.999
6:43200767:T:C	W1194R	0.999
6:43220801:T:C	C2160R	0.999
6:43221194:T:A	W2209R	0.999
6:43221194:T:C	W2209R	0.999
6:43221196:G:C	W2209C	0.999
6:43221196:G:T	W2209C	0.999
6:43221261:T:C	L2231P	0.999

dbSNP variants (sampled 300 via entrez): RS1000271544 (6:43208548 A>G), RS1000305627 (6:43193566 G>T), RS1000308321 (6:43208925 A>C,G), RS1000484936 (6:43224856 T>C), RS1000632278 (6:43187856 G>A), RS1000662822 (6:43219998 G>A), RS1000684720 (6:43188212 G>A), RS1000732193 (6:43218484 G>A), RS1000750179 (6:43214201 C>T), RS1000958606 (6:43220754 A>G), RS1001048129 (6:43207136 G>C), RS1001121673 (6:43182606 C>A,T), RS1001188661 (6:43189294 A>T), RS1001339077 (6:43216893 A>G), RS1001487260 (6:43210916 A>G)

Disease associations

OMIM: gene MIM:607489 | disease phenotypes: MIM:207500, MIM:301800, MIM:614429, MIM:108800

GenCC curated gene-disease

Mondo (5): imperforate anus (MONDO:0001046), ventricular septal defect (MONDO:0002070), arthritic joint disease (MONDO:0005578), atrial septal defect (MONDO:0006664), coronary atherosclerosis (MONDO:0021661)

Orphanet (3): Interatrial communication (Orphanet:1478), Non-syndromic anorectal malformation (Orphanet:557), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001629	Ventricular septal defect

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001762_837	Obesity-related traits	9.000000e-06
GCST007325_195	General risk tolerance (MTAG)	2.000000e-08
GCST008529_28	Tea consumption	3.000000e-06
GCST008899_1	Adult hearing difficulty	6.000000e-21
GCST90020025_725	Waist-to-hip ratio adjusted for BMI	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0010091	tea consumption measurement
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001006	Anus, Imperforate	C06.198.050; C16.131.314.094
D001168	Arthritis	C05.550.114
D006344	Heart Septal Defects, Atrial	C14.240.400.560.375; C14.280.400.560.375; C16.131.240.400.560.375
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523744 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Dexamethasone	decreases expression, affects cotreatment	2
FR900359	decreases phosphorylation	1
bisphenol F	decreases expression, affects cotreatment	1
bufotalin	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
beryllium sulfate	decreases expression, increases expression	1
M-VAC protocol	decreases response to substance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4324644	Binding	Protac activity against VHL/cullin9 in human HT-29 cells harboring with BRAF V600E variant assessed as reduction in Cullin9 protein level at 0.1 uM after 10 hrs by LC-MS based Volcano plot analysis	Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02914652	PHASE4	COMPLETED	The Cardiopulmonary Effect of Inhaled Beta-2-agonists on Adult Patients Born With Ventricular Septum Defects.
NCT05688670	PHASE4	COMPLETED	Regional Anesthesia Following Pediatric Cardiac Surgery
NCT00180206	PHASE4	UNKNOWN	Birmingham Hip Resurfacing (BHR) Study: Implantation of a Hip Resurfacing Endoprosthesis
NCT00236366	PHASE4	COMPLETED	A Study of the Effect on Pain Control of Treatment With Fentanyl, Administered Through the Skin, Compared With Placebo in Patients With Osteoarthritis
NCT00291915	PHASE4	UNKNOWN	Multicenter Randomized Prospective Trial Comparing Methotrexate Alone or in Combination With Adalimumab in Early Arthritis
NCT00510536	PHASE4	COMPLETED	Treatment of Mild to Moderate Joint Pain in Patients With Chronic Plaque Psoriasis Receiving Efalizumab
NCT00524160	PHASE4	COMPLETED	A Study of the Effect on Pain Control of Treatment With Fentanyl, Administered Through the Skin, in Patients With Rheumatoid Arthritis or Osteoarthritis
NCT00696059	PHASE4	COMPLETED	Humira in Rheumatoid Arthritis - Do Bone Erosions Heal?
NCT01027286	PHASE4	COMPLETED	Prospective Evaluation of Vitagel for Reduction in Blood Loss and Pain Following Unilateral Total Knee Arthroplasty
NCT01264965	PHASE4	TERMINATED	Non-cancer Pain and Cognitive Impairment: A Disabling Relationship
NCT01270620	PHASE4	COMPLETED	Desflurane or Propofol Anesthesia in Elderly Obese Patients Undergoing Total Knee Replacement
NCT01275014	PHASE4	UNKNOWN	Corticosteroids as Additive in Temporomandibular Joint (TMJ) Arthrocentesis
NCT01414569	PHASE4	COMPLETED	Dexamethasone for Pain After Shoulder Surgery
NCT02011464	PHASE4	COMPLETED	Evaluation Exparel Delivered in Knee Replacement
NCT02697955	PHASE4	COMPLETED	The Effect of Subsartorial Saphenous Block on Postoperative Pain Following Major Ankle and Hind Foot Surgery
NCT02926651	PHASE4	WITHDRAWN	Single Versus Multi-Dose Oral Tranexamic Acid in Patients at High Risk for Blood Transfusion After Total Joint Arthroplasty
NCT03659318	PHASE4	COMPLETED	Robotic-Assisted Versus Conventional Total Knee Arthroplasty(TKA)
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00113698	PHASE3	TERMINATED	Angiotensin Converting Enzyme Inhibition in Children With Mitral Regurgitation
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT00153660	PHASE3	COMPLETED	Celecoxib Versus Naproxen for Prevention of Recurrent Ulcer Bleeding in Arthritis Patients
NCT00153673	PHASE3	COMPLETED	Effect of Selective COX-2 Inhibition on Ulcer Healing
NCT00211718	PHASE3	UNKNOWN	Intra-Articular Injection of Botulinum Toxin Type A for Shoulder Pain
NCT00313365	PHASE3	WITHDRAWN	Surgical Lavage vs Serial Needle Aspiration for Infected Joints
NCT00365313	PHASE3	COMPLETED	Preventing Recurrent Ulcer Bleeding in Arthritis Patients Using Esomeprazole Plus Celecoxib
NCT00526201	PHASE3	COMPLETED	Help Arthritis With Exercise in West Virginia
NCT00526435	PHASE3	COMPLETED	Evaluation of Walk With Ease in Arthritis
NCT00646178	PHASE3	COMPLETED	Study of the Safety and Efficacy of Adalimumab in Subjects With Moderate to Severely Active Psoriatic Arthritis Subjects With Inadequate Response to Disease Modifying Anti-Rheumatic Drug Therapy
NCT00733902	PHASE3	COMPLETED	Tanezumab in Osteoarthritis of the Knee
NCT00744471	PHASE3	COMPLETED	Tanezumab in Osteoarthritis Of The Hip
NCT00765362	PHASE3	COMPLETED	Mobile - Bearing Knee Study
NCT00784277	PHASE3	COMPLETED	A Study to Compare the Frequency of Constipation Symptoms With Tapentadol Immediate Release (IR) Treatment Versus Oxycodone IR Treatment in Patients With End-stage Joint Disease
NCT00809354	PHASE3	TERMINATED	Long-Term Analgesic Efficacy And Safety Of Tanezumab Alone Or In Combination With Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Versus NSAIDs Alone In Patients With Osteoarthritis Of The Knee Or Hip
NCT00830063	PHASE3	COMPLETED	Tanezumab In Osteoarthritis Of The Knee (2)
NCT01004432	PHASE3	COMPLETED	Golimumab in Rheumatoid Arthritis Participants With an Inadequate Response to Etanercept (ENBREL) or Adalimumab (HUMIRA)
NCT01089725	PHASE3	TERMINATED	Efficacy And Safety Study Of Tanezumab Subcutaneous Administration In Osteoarthritis - A Subcutaneous/Intravenous Bridging Study
NCT01094886	PHASE3	COMPLETED	Switching Drug Therapy for the Prevention of Blood Clot Formation From Enoxaparin to Rivaroxaban After Orthopedic Surgery for Either Total Hip or Total Knee Replacement
NCT01615991	PHASE3	COMPLETED	Multicentre Canadian Study to Measure the Safety and Efficacy of Radiosynoviorthesis
NCT02202967	PHASE3	COMPLETED	Misoprostol for Small Bowel Ulcers and Obscure Bleeding Due to Aspirin or Nonsteroidal Antiinflammatory Drugs