SPAG9

Summary

SPAG9 (sperm associated antigen 9, HGNC:14524) is a protein-coding gene on chromosome 17q21.33, encoding C-Jun-amino-terminal kinase-interacting protein 4 (O60271). The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module.

This gene encodes a member of the cancer testis antigen gene family. The encoded protein functions as a scaffold protein that structurally organizes mitogen-activated protein kinases and mediates c-Jun-terminal kinase signaling. This protein also binds to kinesin-1 and may be involved in microtubule-based membrane transport. This protein may play a role in tumor growth and development. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 9043 — RefSeq curated summary.

At a glance

• Gene–disease (curated): schizophrenia (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 182 total
• MANE Select transcript: NM_001130528

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14524
Approved symbol	SPAG9
Name	sperm associated antigen 9
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	HSS, SYD1, KIAA0516, MGC14967, MGC74461, MGC117291, JLP, PHET, HLC4, FLJ13450, FLJ14006, FLJ26141, FLJ34602, CT89, JIP4, JIP-4, PIG6
Ensembl gene	ENSG00000008294
Ensembl biotype	protein_coding
OMIM	605430
Entrez	9043

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 26 protein_coding, 10 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000262013, ENST00000357122, ENST00000502329, ENST00000505173, ENST00000505279, ENST00000506483, ENST00000506500, ENST00000509724, ENST00000510283, ENST00000510855, ENST00000511312, ENST00000511795, ENST00000511987, ENST00000513547, ENST00000513746, ENST00000513827, ENST00000513906, ENST00000514205, ENST00000514613, ENST00000515685, ENST00000576492, ENST00000855101, ENST00000855102, ENST00000855103, ENST00000855104, ENST00000855105, ENST00000855106, ENST00000855107, ENST00000855108, ENST00000855109, ENST00000855110, ENST00000933646, ENST00000933647, ENST00000948171, ENST00000948172, ENST00000948173, ENST00000948174, ENST00000948175, ENST00000948176, ENST00000948177

RefSeq mRNA: 4 — MANE Select: NM_001130528 NM_001130527, NM_001130528, NM_001251971, NM_003971

CCDS: CCDS11577, CCDS45740, CCDS58577, CCDS58578

Canonical transcript exons

ENST00000262013 — 30 exons

Exon	Start	End
ENSE00000820065	50989677	50989872
ENSE00001148883	50984923	50984990
ENSE00001274410	50974771	50974947
ENSE00001370042	50985698	50985778
ENSE00001384211	50987112	50987237
ENSE00001418272	50962174	50966387
ENSE00001696138	51079584	51079704
ENSE00003464414	51031681	51031722
ENSE00003480279	50998444	50998617
ENSE00003484552	51056412	51056482
ENSE00003508737	50979746	50979917
ENSE00003519016	51021158	51021365
ENSE00003525010	51005212	51005263
ENSE00003532157	50970707	50970856
ENSE00003556844	51007269	51007326
ENSE00003558894	50995057	50995224
ENSE00003575446	51001715	51001845
ENSE00003593436	50977108	50977221
ENSE00003609426	50990450	50990668
ENSE00003627855	51041501	51041651
ENSE00003630580	51020159	51020258
ENSE00003634834	50995444	50995533
ENSE00003650712	50982524	50982672
ENSE00003651010	51014232	51014353
ENSE00003663888	50999661	50999717
ENSE00003676571	50996565	50996694
ENSE00003683607	51047375	51047469
ENSE00003687608	50993764	50993935
ENSE00003690845	51006085	51006237
ENSE00003850676	51120354	51120868

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.0555 / max 1435.3614, expressed in 1822 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167027	42.3483	1822
167016	4.0612	419
167012	3.3813	331
167026	2.5547	942
167014	2.1989	419
167013	0.9934	260
167009	0.3337	140
167010	0.3193	160
167019	0.1852	61
167015	0.1791	75

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.42	gold quality
ventricular zone	UBERON:0003053	98.80	gold quality
ganglionic eminence	UBERON:0004023	98.61	gold quality
sural nerve	UBERON:0015488	98.61	gold quality
corpus callosum	UBERON:0002336	98.50	gold quality
medial globus pallidus	UBERON:0002477	98.12	gold quality
globus pallidus	UBERON:0001875	97.88	gold quality
inferior vagus X ganglion	UBERON:0005363	97.69	gold quality
endothelial cell	CL:0000115	97.65	gold quality
cartilage tissue	UBERON:0002418	97.65	gold quality
subthalamic nucleus	UBERON:0001906	97.62	gold quality
colonic epithelium	UBERON:0000397	97.36	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.25	gold quality
nerve	UBERON:0001021	97.20	gold quality
tibial nerve	UBERON:0001323	97.20	gold quality
spinal cord	UBERON:0002240	96.81	gold quality
right lung	UBERON:0002167	96.78	gold quality
adrenal tissue	UBERON:0018303	96.69	gold quality
tendon	UBERON:0000043	96.50	gold quality
medulla oblongata	UBERON:0001896	96.44	gold quality
superior vestibular nucleus	UBERON:0007227	96.44	gold quality
pons	UBERON:0000988	96.40	gold quality
lateral globus pallidus	UBERON:0002476	96.32	gold quality
cortical plate	UBERON:0005343	96.14	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.13	gold quality
mucosa of stomach	UBERON:0001199	96.11	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.06	gold quality
trigeminal ganglion	UBERON:0001675	96.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.97	gold quality
primary visual cortex	UBERON:0002436	95.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8271	no	148.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1

miRNA regulators (miRDB)

242 targeting SPAG9, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
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-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-3658	99.96	73.87	4379

Literature-anchored findings (GeneRIF, showing 40)

• Testicular antigen PHET is an auutoantigen recognized by sera from systemic sclerosis (SSc) patients with extensive fibrotic changes; the autoantibody response to PHET is induced by ectopic overexpression of PHET in dermal fibroblasts of SSc patients. (PMID:14662895)
• first report of sperm-associated JNK-binding protein (SPAG9) that may have a role in spermatozoa-egg interaction (PMID:15693750)
• SPAG9 is a new member of c-Jun NH2 -terminal kinase (JNK) interacting protein exclusively expressed in testis (PMID:16077255)
• The present investigation will eventually extend the application of SPAG9 siRNA in in vivo targeting experiments that aim to define the SPAG9 functional genomics in tumor and reproductive biology. (PMID:16356479)
• Recombinant human protein is adsorbed on alum is highly immunogenic in macaca model and therefore represents a suitable sperm-based vaccine immunogen for fertility trials in macaque. (PMID:16959808)
• SPAG9 may have a role in tumor development and metastasis and thus could serve as a novel target for early detection and treatment of renal cell carcinoma. (PMID:18922895)
• Kinesin adapter JLP links PIKfyve to microtubule-based endosome-to-trans-Golgi network traffic of furin. (PMID:19056739)
• structural analysis of ARF6 in a complex with JIP4 (PMID:19644450)
• Findings support a potential role for SPAG9 as diagnostic biomarker as well as a possible therapeutic target in thyroid cancer treatment. (PMID:19820019)
• SPAG9 protein is found in the equatorial plate and flagella of human spermatozoa. (PMID:19947555)
• SPAG9 mRNA& protein are expressed in CML patients (88%) and in K562 & KCL-22 cells. 90% CML chronic-phase patients showed humoral response against SPAG9. (PMID:20138665)
• N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK (PMID:21177868)
• These findings collectively suggest that SPAG9 may have a role in tumor development and early spread. (PMID:21356354)
• SPAG9 is positively expressed in endometrial cancer, and with a high humoral immune response in patients. It may serve as a new type of endometrial cancer markers for early detection, diagnosis and treatment. (PMID:22146769)
• SPAG9 serves as an important oncoprotein in human astrocytoma by regulating cell proliferation and invasion. (PMID:23696027)
• SPAG9 depletion could inhibit the activity of p-JNK. (PMID:23711689)
• down regulation of SPAG9 reduces growth and invasive potential of triple-negative breast cancer cells, suggesting that SPAG9 may be a potential target for therapeutic use. (PMID:24330581)
• data in clinical specimens indicated that SPAG9 is potential biomarker and therapeutic target for bladder TCC. (PMID:24349057)
• High SPAG9 expression is associated with endometrial cancer. (PMID:24460345)
• SPAG9 is overexpressed in human prostate cancers and contributes to prostate cancer cell growth, possibly through cyclin protein regulation. (PMID:24740566)
• SPAG9 upregulates PODXL expression in human astrocytoma cells at the PODXL gene promoter/transcriptional level through a JNKdependent mechanism. (PMID:24788963)
• SPAG9 is overexpressed in human HCC and serves as a prognostic marker. SPAG9 contributes to cancer cell growth through regulation of cyclin proteins. (PMID:24801907)
• SPAG9 was upregulated in nonmelanoma skin cancer when compared with normal skin. (PMID:25033008)
• knockdown of Sec8 enhances the binding of JIP4 to MAPK kinase 4, thereby decreasing the phosphorylation of MAPK kinase 4, JNK, and p38. (PMID:25244576)
• SPAG9 expression is significantly increased in prostate cancer and it may be involved in the process of prostate cancer cell motility, migration and angiogenesis. (PMID:25310386)
• PLK1 binding to JIP4 was found in G2 phase and mitosis, and PLK1 binding was self-primed by PLK1 phosphorylation of JIP4. (PMID:26291670)
• SPAG9 overexpression in gastric cancer correlates with poor prognosis and contributes to gastric cancer cell proliferation (PMID:26293216)
• FOXK1 protein levels and activity are regulated by associating with JLP and PLK1 (PMID:26468278)
• SPAG9-elevated expression contributes to malignant behavior and poor prognosis of breast cancer and may support a potential indicator in treatment selection. (PMID:26631164)
• Study suggest that suppression of miR-141 may cause an aberrant overexpression of SPAG9 promoting growth and metastasis of hepatocellular carcinoma cells. (PMID:26790956)
• Based on in vitro assays, we found miR-200a-3p significantly inhibit cancer cell proliferation by inducing apoptosis. (PMID:26797273)
• SPAG9 mRNA and protein overexpression in lung cancer tissue, and the presence of SPAG9 IgG antibody in peripheral blood of lung cancer patients indicates that it has potential as a biomarker for lung cancer diagnosis. (PMID:26934841)
• expression of SPAG9 in ECC cells with TGF-beta1 treatment and spheroids formation was increased (PMID:27352556)
• Aberrant expression of JNK-associated leucine-zipper protein, JLP, promotes accelerated growth of ovarian cancer (PMID:27655714)
• these data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions. (PMID:29146937)
• AKAP4 and SPAG9 genes may find use as diagnostic biomarkers for CRC. (PMID:29480665)
• High SPAG9 expression is associated with drug resistance in anaplastic thyroid carcinoma. (PMID:31485599)
• Structural characterization of the RH1-LZI tandem of JIP3/4 highlights RH1 domains as a cytoskeletal motor-binding motif. (PMID:31690808)
• Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway. (PMID:32776977)
• Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons. (PMID:33788575)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	spag9a	ENSDARG00000074531
danio_rerio	SPAG9	ENSDARG00000078142
mus_musculus	Spag9	ENSMUSG00000020859
rattus_norvegicus	Spag9	ENSRNOG00000002749
drosophila_melanogaster	syd	FBGN0024187
caenorhabditis_elegans		WBGENE00006755

Paralogs (1): MAPK8IP3 (ENSG00000138834)

Protein

Protein identifiers

C-Jun-amino-terminal kinase-interacting protein 4 — O60271 (reviewed: O60271)

Alternative names: Cancer/testis antigen 89, Human lung cancer oncogene 6 protein, JNK-associated leucine-zipper protein, Mitogen-activated protein kinase 8-interacting protein 4, Proliferation-inducing protein 6, Protein highly expressed in testis, Sperm surface protein, Sperm-associated antigen 9, Sperm-specific protein, Sunday driver 1

All UniProt accessions (5): O60271, D6RHI8, H0Y981, H0YBE9, H0YBS5

UniProt curated annotations — full annotation on UniProt →

Function. The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Regulates lysosomal positioning by acting as an adapter protein which links PIP4P1-positive lysosomes to the dynein-dynactin complex. Assists PIKFYVE selective functionality in microtubule-based endosome-to-TGN trafficking.

Subunit / interactions. Homodimer. The homodimer interacts with ARF6, forming a heterotetramer. Homooligomer. Interacts with MAX, MAPK14, MAP3K3, MYC, KNS2 and MAP2K4. Interaction with KNS2 is important in the formation of ternary complex with MAPK8. Interacts with NFKB1. Interacts with PIP4P1. Interacts with PIKFYVE. Interacts with MAPK8, MAPK9, MAPK10.

Subcellular location. Cytoplasm. Perinuclear region. Lysosome membrane Cytoplasmic vesicle. Secretory vesicle. Acrosome.

Tissue specificity. Expressed only in testis on the round spermatids of stage I, II and II. Absent in spermatogonia and spermatocyte. Expressed in testis and in acute myeloid leukemia (AML) patients. Expressed in testis.

Post-translational modifications. Phosphorylated by MAPK8 and MAPK14.

Activity regulation. May play a role in spermatozoa-egg-interaction.

Induction. Increased in systemic sclerosis fibroblasts.

Miscellaneous. Due to intron retention.

Similarity. Belongs to the JIP scaffold family.

Isoforms (6)

UniProt ID	Names	Canonical?
O60271-1	1, JLP(L)	yes
O60271-2	2
O60271-3	3
O60271-4	4
O60271-5	5
O60271-9	6

RefSeq proteins (4): NP_001123999, NP_001124000, NP_001238900, NP_003962 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR032486	JIP_LZII	Domain
IPR034743	RH1	Domain
IPR034744	RH2	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR039911	JIP3/JIP4	Family

Pfam: PF09744, PF16471, PF19056

UniProt features (58 total): modified residue 30, compositionally biased region 6, splice variant 6, region of interest 5, coiled-coil region 3, sequence conflict 3, domain 2, chain 1, sequence variant 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2W83	X-RAY DIFFRACTION	1.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60271-F1	65.41	0.35

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 (30): 1, 109, 183, 185, 194, 203, 217, 238, 251, 265, 268, 272, 292, 311, 329, 332, 347, 348, 365, 418 …

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-525793	Myogenesis
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 395 (showing top): ATF_B, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, GCM_MAP4K4, RRAGTTGT_UNKNOWN, TAATAAT_MIR126, RORA1_01, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, CMYB_01, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GCM_ZNF198, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS

GO Biological Process (10): vesicle-mediated transport (GO:0016192), positive regulation of cell migration (GO:0030335), lysosome localization (GO:0032418), retrograde transport, endosome to Golgi (GO:0042147), positive regulation of MAPK cascade (GO:0043410), negative regulation of neuron differentiation (GO:0045665), positive regulation of neuron differentiation (GO:0045666), striated muscle cell differentiation (GO:0051146), negative regulation of dendrite extension (GO:1903860), MAPK cascade (GO:0000165)

GO Molecular Function (6): MAP kinase scaffold activity (GO:0005078), JUN kinase binding (GO:0008432), kinesin binding (GO:0019894), signaling receptor complex adaptor activity (GO:0030159), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (10): acrosomal vesicle (GO:0001669), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829), centriolar satellite (GO:0034451), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), lysosome (GO:0005764), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
MAPK cascade	2
neuron differentiation	2
regulation of neuron differentiation	2
signaling adaptor activity	2
transport	1
cellular process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
vacuolar localization	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
negative regulation of cell differentiation	1
positive regulation of cell differentiation	1
muscle cell differentiation	1
negative regulation of cell growth	1
negative regulation of developmental growth	1
dendrite extension	1
regulation of dendrite extension	1
intracellular signaling cassette	1
mitogen-activated protein kinase binding	1
protein complex scaffold activity	1
protein kinase binding	1
cytoskeletal protein binding	1
signaling receptor binding	1
protein binding	1
binding	1
secretory granule	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
centrosome	1
extracellular vesicle	1
lytic vacuole	1
intracellular vesicle	1

Protein interactions and networks

STRING

1606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAG9	PIP4P1	Q86T03	974
SPAG9	ARF6	P26438	933
SPAG9	HYAL3	O43820	891
SPAG9	SPAM1	P38567	886
SPAG9	HYAL2	Q12891	818
SPAG9	MAPK8IP1	Q9UQF2	790
SPAG9	KLC1	Q07866	782
SPAG9	MAPK8IP2	Q13387	762
SPAG9	POLG	P54098	749
SPAG9	JUN	P05412	732
SPAG9	DCTN1	Q14203	695
SPAG9	MAPK8	P45983	651
SPAG9	MAP2K7	O14733	624
SPAG9	RAB10	P61026	620
SPAG9	POLG2	Q9UHN1	589

IntAct

171 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NFKB1	SPAG9	psi-mi:“MI:0915”(physical association)	0.690
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
MAPK8IP3	RCCD1	psi-mi:“MI:0914”(association)	0.640
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
SPAG9	RAB8A	psi-mi:“MI:0915”(physical association)	0.620
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
NFKB1	NFKBIE	psi-mi:“MI:2364”(proximity)	0.600
PLK1	C1orf226	psi-mi:“MI:0914”(association)	0.560
SPAG9	EXOC4	psi-mi:“MI:0915”(physical association)	0.560
EXOC4	SPAG9	psi-mi:“MI:0403”(colocalization)	0.560
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CACNG5	ZNF316	psi-mi:“MI:0914”(association)	0.530
BMERB1	DCTN6	psi-mi:“MI:0914”(association)	0.530
MAPK8IP3	DCTN6	psi-mi:“MI:0914”(association)	0.530
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530

BioGRID (340): SPAG9 (Affinity Capture-Western), SPAG9 (Affinity Capture-Western), ABL1 (Affinity Capture-Western), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Proximity Label-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS)

ESM2 similar proteins: A0A088MLT8, A0A0G2K0D3, A2AQ19, B3KU38, D3ZTQ1, E1BTG2, E6ZGB4, E9PSK7, O35274, O60271, O75151, O75376, P12755, P22682, P29536, P49140, Q08DA0, Q13191, Q3B7T9, Q3TTA7, Q3UHZ5, Q3USH5, Q3YEC7, Q4KKX4, Q58A65, Q5SFM8, Q5U3K5, Q60698, Q60974, Q62415, Q640N2, Q6P5Q4, Q6R891, Q70E73, Q80XA6, Q86YP4, Q8BVA4, Q8CHY6, Q8K4S7, Q8R3Y5

Diamond homologs: A2AWP8, E9PSK7, O60271, P34609, Q29EP6, Q29RM4, Q58A65, Q5R5M3, Q80U35, Q9ESN9, Q9GQF1, Q9HCE6, Q9UPT6, Q8C033

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
SPAG9	“form complex”	CDON/SPAG9	binding
SPAG9	“up-regulates activity”	MAPK14	binding
SPAG9	up-regulates	MAPK11	binding
CDON	“up-regulates activity”	SPAG9	binding
SPAG9	unknown	ABL1	binding
SPAG9	unknown	MAP3K5	binding
SPAG9	unknown	MAP3K7	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 193 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of the pre-replicative complex	5	13.7×	6e-03
Activation of ATR in response to replication stress	5	12.6×	6e-03
S Phase	6	9.1×	6e-03
Clathrin-mediated endocytosis	8	5.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	135
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

4682 predictions. Top by Δscore:

Variant	Effect	Δscore
17:50966387:CCT:C	acceptor_loss	1.0000
17:50970702:CATA:C	donor_loss	1.0000
17:50970703:ATACC:A	donor_loss	1.0000
17:50970704:TACCC:T	donor_loss	1.0000
17:50970705:A:AC	donor_gain	1.0000
17:50970705:A:T	donor_loss	1.0000
17:50970705:AC:A	donor_gain	1.0000
17:50970706:C:CC	donor_gain	1.0000
17:50970706:CC:C	donor_gain	1.0000
17:50977106:A:AC	donor_gain	1.0000
17:50977107:C:CT	donor_gain	1.0000
17:50977107:CT:C	donor_gain	1.0000
17:50977107:CTTT:C	donor_gain	1.0000
17:50979918:C:CC	acceptor_gain	1.0000
17:50982669:CCAT:C	acceptor_gain	1.0000
17:50982670:CATC:C	acceptor_gain	1.0000
17:50982673:C:CC	acceptor_gain	1.0000
17:50982675:T:C	acceptor_gain	1.0000
17:50985697:CA:C	donor_gain	1.0000
17:50985775:CAAA:C	acceptor_gain	1.0000
17:50987107:CCTA:C	donor_loss	1.0000
17:50987108:CTACC:C	donor_loss	1.0000
17:50987109:TA:T	donor_loss	1.0000
17:50987110:A:AC	donor_gain	1.0000
17:50987110:ACC:A	donor_loss	1.0000
17:50987110:ACCAG:A	donor_gain	1.0000
17:50987111:C:CC	donor_gain	1.0000
17:50987111:C:CG	donor_loss	1.0000
17:50987111:CCA:C	donor_gain	1.0000
17:50987111:CCAG:C	donor_gain	1.0000

AlphaMissense

8676 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:50966298:A:G	W1314R	1.000
17:50966298:A:T	W1314R	1.000
17:50970714:G:C	F1281L	1.000
17:50970714:G:T	F1281L	1.000
17:50970716:A:G	F1281L	1.000
17:50970736:C:T	G1274E	1.000
17:50970738:A:C	S1273R	1.000
17:50970738:A:T	S1273R	1.000
17:50970740:T:G	S1273R	1.000
17:50974809:C:T	G1221E	1.000
17:50974810:C:A	G1221W	1.000
17:50974814:G:C	F1219L	1.000
17:50974814:G:T	F1219L	1.000
17:50974816:A:G	F1219L	1.000
17:50974821:A:G	L1217P	1.000
17:50977126:A:G	S1169P	1.000
17:50977137:C:A	G1165V	1.000
17:50977137:C:T	G1165D	1.000
17:50977138:C:G	G1165R	1.000
17:50977149:C:T	G1161E	1.000
17:50977150:C:A	G1161W	1.000
17:50977150:C:G	G1161R	1.000
17:50977150:C:T	G1161R	1.000
17:50977156:A:G	W1159R	1.000
17:50977156:A:T	W1159R	1.000
17:50977158:A:G	L1158S	1.000
17:50977161:C:G	R1157P	1.000
17:50977202:G:C	F1143L	1.000
17:50977202:G:T	F1143L	1.000
17:50977204:A:G	F1143L	1.000

dbSNP variants (sampled 300 via entrez): RS1000023392 (17:51062845 C>T), RS1000054564 (17:51062593 T>C), RS1000058655 (17:51027703 A>C,G,T), RS1000064779 (17:51095783 G>A), RS1000067412 (17:50964343 T>G), RS1000074908 (17:51030540 T>G), RS1000089935 (17:51111031 G>A), RS1000095236 (17:51046859 G>A,C), RS1000099577 (17:51115305 TA>T), RS1000104191 (17:51104694 A>G), RS1000111677 (17:50972698 T>C), RS1000136815 (17:51089946 G>A,C), RS1000190230 (17:50963248 C>A,T), RS1000194158 (17:50991559 C>T), RS1000201676 (17:51086179 T>A,C)

Disease associations

OMIM: gene MIM:605430 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
schizophrenia	Limited	Autosomal dominant

Mondo (1): schizophrenia (MONDO:0005090)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006979_504	Heel bone mineral density	3.000000e-12
GCST008157_45	Body fat mass	1.000000e-06
GCST009391_1440	Metabolite levels	2.000000e-06
GCST009391_1820	Metabolite levels	9.000000e-06
GCST009391_517	Metabolite levels	2.000000e-06
GCST010106_2	Conjunctival UV autofluorescence (CUVAF)	1.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0010409	triacylglycerol 50:2 measurement
EFO:0010404	triacylglycerol 48:1 measurement
EFO:0010117	pyruvate measurement
EFO:0004731	eye measurement
EFO:0010729	sun exposure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment, decreases expression	7
trichostatin A	affects cotreatment, decreases expression, affects expression	4
Ozone	affects expression, affects cotreatment, increases oxidation, increases abundance	3
bisphenol A	affects expression, affects cotreatment, affects methylation	2
arsenite	affects expression, affects binding, decreases reaction	2
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	2
entinostat	decreases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Cyclosporine	increases expression	2
Asbestos, Crocidolite	decreases methylation, increases expression	2
Cadmium Chloride	increases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	increases activity, affects binding, decreases expression	1
2-butenal	increases expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
coumarin	affects phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1QP	Abcam K-562 SPAG9 KO	Cancer cell line	Female
CVCL_D2MA	Abcam Raji SPAG9 KO	Cancer cell line	Male
CVCL_E2KN	HAP1 SPAG9 (-) 2	Cancer cell line	Male
CVCL_WQ58	Abcam Jurkat SPAG9 KO	Cancer cell line	Male
CVCL_XT69	HAP1 SPAG9 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety