SEPTIN4

Summary

SEPTIN4 (septin 4, HGNC:9165) is a protein-coding gene on chromosome 17q22, encoding Septin-4 (O43236). Filament-forming cytoskeletal GTPase.

This gene is a member of the septin family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse, and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. This gene is highly expressed in brain and heart. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. One of the isoforms (known as ARTS) is distinct; it is localized to the mitochondria, and has a role in apoptosis and cancer.

Source: NCBI Gene 5414 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 103 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001368771

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9165
Approved symbol	SEPTIN4
Name	septin 4
Location	17q22
Locus type	gene with protein product
Status	Approved
Aliases	H5, CE5B3, hucep-7, ARTS, hCDCREL-2, MART, FLJ40121, Septin-4
Ensembl gene	ENSG00000108387
Ensembl biotype	protein_coding
OMIM	603696
Entrez	5414

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 17 protein_coding, 10 retained_intron, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000317256, ENST00000317268, ENST00000321691, ENST00000393086, ENST00000412945, ENST00000426861, ENST00000457347, ENST00000577440, ENST00000577729, ENST00000578131, ENST00000578747, ENST00000579371, ENST00000580740, ENST00000580791, ENST00000580796, ENST00000580809, ENST00000580844, ENST00000581607, ENST00000581615, ENST00000581921, ENST00000582248, ENST00000582270, ENST00000582976, ENST00000583114, ENST00000583273, ENST00000583291, ENST00000584488, ENST00000584528, ENST00000584789, ENST00000585170, ENST00000671766, ENST00000672673, ENST00000672699

RefSeq mRNA: 10 — MANE Select: NM_001368771 NM_001038704, NM_001198713, NM_001256782, NM_001256822, NM_001363803, NM_001368771, NM_001368772, NM_004574, NM_080415, NM_080416

CCDS: CCDS11609, CCDS11610, CCDS32691, CCDS45743, CCDS56041, CCDS58581, CCDS58582, CCDS86620, CCDS92368

Canonical transcript exons

ENST00000672673 — 14 exons

Exon	Start	End
ENSE00003459392	58521545	58521646
ENSE00003498473	58521736	58521853
ENSE00003520175	58520743	58520842
ENSE00003547345	58526220	58526313
ENSE00003553557	58526682	58526978
ENSE00003558529	58520998	58521160
ENSE00003573399	58520256	58520485
ENSE00003592032	58521967	58522101
ENSE00003610780	58525695	58525781
ENSE00003686232	58521254	58521350
ENSE00003790757	58525078	58525201
ENSE00003891806	58541922	58541966
ENSE00003894404	58540666	58540673
ENSE00003894557	58542626	58544328

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 99.76.

FANTOM5 (CAGE): breadth broad, TPM avg 13.8130 / max 914.0186, expressed in 748 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167293	11.1133	731
167290	1.2678	107
167283	0.2932	71
167292	0.2478	68
167284	0.2126	70
167288	0.1805	56
167291	0.1526	55
167296	0.1268	67
167286	0.0458	35
167282	0.0410	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.70	gold quality
cerebellar hemisphere	UBERON:0002245	99.66	gold quality
cerebellar cortex	UBERON:0002129	99.65	gold quality
middle frontal gyrus	UBERON:0002702	99.51	gold quality
cerebellum	UBERON:0002037	99.50	gold quality
paraflocculus	UBERON:0005351	99.50	gold quality
corpus callosum	UBERON:0002336	99.48	gold quality
lateral globus pallidus	UBERON:0002476	99.40	gold quality
globus pallidus	UBERON:0001875	99.30	gold quality
right frontal lobe	UBERON:0002810	99.30	gold quality
medial globus pallidus	UBERON:0002477	99.28	gold quality
spinal cord	UBERON:0002240	99.26	gold quality
putamen	UBERON:0001874	99.20	gold quality
inferior vagus X ganglion	UBERON:0005363	99.11	gold quality
amygdala	UBERON:0001876	99.06	gold quality
hypothalamus	UBERON:0001898	98.89	gold quality
nucleus accumbens	UBERON:0001882	98.85	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.84	gold quality
caudate nucleus	UBERON:0001873	98.81	gold quality
cingulate cortex	UBERON:0003027	98.80	gold quality
anterior cingulate cortex	UBERON:0009835	98.80	gold quality
subthalamic nucleus	UBERON:0001906	98.75	gold quality
cranial nerve II	UBERON:0000941	98.73	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.59	gold quality
prefrontal cortex	UBERON:0000451	98.57	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.53	gold quality
substantia nigra pars compacta	UBERON:0001965	98.41	gold quality
right adrenal gland cortex	UBERON:0035827	98.38	gold quality
pons	UBERON:0000988	98.32	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	20.83
E-MTAB-8410	yes	16.92
E-GEOD-84465	yes	14.73
E-ANND-3	yes	9.66
E-GEOD-137537	yes	8.40

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 35)

• role of Bradeion in colorectal neoplasms (PMID:12032658)
• Sept4 is involved in the formation of cytoplasmic inclusions as well as induction of cell death in alpha-synuclein-associated neurodegenerative disorders. (PMID:12695511)
• Data suggest that ARTS induces apoptosis by antagonizing IAPs, including XIAP. (PMID:15029247)
• SEPT8 and SEPT4 are localized surrounding alpha-granules. Activation of platelets by agonists resulted in the translocation of SEPT4 and SEPT8 to the platelet surface indicating a possible functional role of these proteins in platelet granular secretion (PMID:15116257)
• ARTS can function as a tumor suppressor protein in childhood acute lymphocytic leukemia. (PMID:15122323)
• We studied the assembly of three human septins, SEPT4, SEPT5 and SEPT8, with each other (heterotypic) and with themselves (homotypic) using a yeast two-hybrid system. (PMID:15214843)
• high cellular levels of ARTS protein sensitize cells toward apoptosis (PMID:15837787)
• The data presented here suggest that ARTS P-loop is not frequently mutated in gastric, lung, and hepatocellular carcinomas, and that apoptosis deregulation in cancers is not dependent on the mutation of ARTS gene. (PMID:16376484)
• Finds somatic mutation in P-loop domains of proapoptotic ARTS genes uncommon in colon cancers. (PMID:16464805)
• define explicitly and characterize the domains of human SEPT4 (PMID:17105210)
• The Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity. (PMID:17296554)
• interaction of kaposin A protein and the septin 4 variant was suggested as playing a possible role in the development of HHV-8-associated malignancies (PMID:17383018)
• SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling (PMID:17546647)
• This protein may play an important role in the pathogenesis of schizophrenia and could be used as a marker for this disease. (PMID:17644312)
• Data report an intermediate structure of the GTPase domain of human SEPT4 (SEPT4-G) during unfolding transitions induced by temperature. (PMID:17764158)
• The stability and aggregation properties of the GTPase domain from human SEPT4. (PMID:18617022)
• Sporadic PD cases showed a statistically significant decrease of the fold change (FC) of SEPT4 (FC = 0.67, P = 0.054) gene expressions in the substantia nigra & amygdala (SEPT4: FC = 0.32, P = 0.007) versus healthy controls. (PMID:18951507)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• structural defects in sperm are not caused by abnormal transcription or point mutations of the TAT1 and SEPT4 genes; however, although both proteins are expressed, they are not properly localized at sperm annulus (PMID:19221096)
• ARTS is localized at mitochondria and promotes programmed cell death (apoptosis). (PMID:21824006)
• The expression of SEPT4 is significantly decreased in the ejaculated sperm of idiopathic asthenozoospermia patients. (PMID:21898991)
• SEPT4 is a Notch target gene. (PMID:21938432)
• these data suggests a tumor suppressor role of SEPT4_i1 in HCC through regulating hepatocellular carcinoma cell apoptosis. (PMID:21952823)
• Bradeion/SEPT4 transcript levels are significantly increased in patients with transitional cell bladder cancer.We hypothesize that Bradeion is directly involved in bladder cancer pathogenesis with the highest expression at early cancer stages. (PMID:22503047)
• results suggest that Septin4 may be involved in the process of activation of hepatic stellate cells by lipopolysaccharide stimulation. (PMID:23180367)
• Identification of a novel anti-apoptotic E3 ubiquitin ligase that ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, and ARTS. (PMID:23479728)
• The data suggest that Sept4_i1 induces hepatic stellate cell apoptosis by inhibiting Akt and Bcl-2 expression and up-regulating PPAR-gamma expression. (PMID:25527525)
• carnosic acid induces parkin by enhancing the ubiquitination of ARTS, leading to induction of XIAP. (PMID:28224479)
• Septin4 is a novel essential factor involved in oxidative stress induced vascular endothelial cell injury by interacting with apoptosis-related protein PARP1. (PMID:29366480)
• In this review, we will discuss the recent advances of the tauopathy research, primarily focusing on its association with the early axonal manifestation of axonal transport defect, axonal mitochondrial stress, autophagic vesicle accumulation and the proceeding of axon destruction, and the pathogenic Tau spreading across the synapse. (PMID:29991349)
• Role of WW domain E3 ubiquitin protein ligase 2 in modulating ubiquitination and Degradation of Septin4 in oxidative stress endothelial injury. (PMID:31924572)
• Septin4 regulates endoplasmic reticulum stress and apoptosis in melatonininduced osteoblasts. (PMID:32626973)
• p53 induces ARTS to promote mitochondrial apoptosis. (PMID:33627621)
• Biallelic loss-of-function mutations in SEPTIN4 (C17ORF47), encoding a conserved annulus protein, cause thin midpiece spermatozoa and male infertility in humans. (PMID:36135717)
• The ARTS of p53-dependent mitochondrial apoptosis. (PMID:36565718)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Septin-4 — O43236 (reviewed: O43236)

Alternative names: Bradeion beta, Brain protein H5, CE5B3 beta, Cell division control-related protein 2, Peanut-like protein 2

All UniProt accessions (10): O43236, A0A5F9ZHS9, J3KS26, J3KS85, J3KSZ7, J3QLA8, J3QLR2, J3QRS4, J3QRT6, J3QRU3

UniProt curated annotations — full annotation on UniProt →

Function. Filament-forming cytoskeletal GTPase. Pro-apoptotic protein involved in LGR5-positive intestinal stem cell and Paneth cell expansion in the intestines, via its interaction with XIAP. May also play a role in the regulation of cell fate in the intestine. Positive regulator of apoptosis involved in hematopoietic stem cell homeostasis; via its interaction with XIAP. Negative regulator of repair and hair follicle regeneration in response to injury, due to inhibition of hair follicle stem cell proliferation, potentially via its interaction with XIAP. Plays an important role in male fertility and sperm motility. During spermiogenesis, essential for the establishment of the annulus (a fibrous ring structure connecting the midpiece and the principal piece of the sperm flagellum) which is a requisite for the structural and mechanical integrity of the sperm. Involved in the migration of cortical neurons and the formation of neuron leading processes during embryonic development. Required for dopaminergic metabolism in presynaptic autoreceptors; potentially via activity as a presynaptic scaffold protein. Required for the induction of cell death mediated by TGF-beta and possibly by other apoptotic stimuli. Induces apoptosis through binding and inhibition of XIAP resulting in significant reduction in XIAP levels, leading to caspase activation and cell death. Mediates the interaction between BCL2 and XIAP, thereby positively regulating the ubiquitination and degradation of BCL2 and promoting apoptosis.

Subunit / interactions. Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation. Interacts with SEPTIN8. In a mesenchymal cell line, interacts with SEPTIN9 isoform 2 variants HNA Trp-106 and Phe-111, but not the wild type SEPTIN9. Component of a septin core octameric complex consisting of SEPTIN12, SEPTIN7, SEPTIN6 and SEPTIN2 or SEPTIN4 in the order 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12. Interacts with SEPTIN14 (via C-terminus). Interacts with DYRK1A. Interacts with SLC6A3/DAT and SNCA/alpha-synuclein. Interacts with STX1A; in the striatum. Interacts with XIAP (via BIR3 domain) following the induction of apoptosis. Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis. Part of a complex composed of SEPTIN4 isoform ARTS, XIAP and BCL2, within the complex interacts with both BCL2 (via BH3 domain) and XIAP, ARTS acts as a scaffold protein and stabilizes the complex. Interacts with XIAP (via BIR3 domain) following the induction of apoptosis.

Subcellular location. Cytoplasm. Cell projection. Cilium. Flagellum. Cytoplasmic vesicle. Secretory vesicle. Axon. Dendrite. Perikaryon. Synapse Mitochondrion. Nucleus.

Tissue specificity. Widely expressed in adult and fetal tissues with highest expression in adult brain (at protein level), heart, liver and adrenal gland and fetal heart, kidney, liver and lung. Expressed in presynaptic terminals of dopaminergic neurons projecting from the substantia nigra pars compacta to the striatum (at protein level). Expressed in axonal varicosities in dopaminergic nerve terminals (at protein level). Expressed in the putamen and in the adjacent cerebral cortex (at protein level). Expressed in colonic crypts (at protein level). Expressed in platelets. Expressed in spermatozoa (at protein level). Highly expressed in the brain and heart.

Post-translational modifications. Phosphorylated by DYRK1A. Ubiquitinated by AREL1.

Disease relevance. Spermatogenic failure 99 (SPGF99) [MIM:621194] An autosomal recessive, male infertility disorder characterized by asthenoteratozoospermia with markedly reduced sperm progressive motility, and abnormal sperm morphology. Patient sperm exhibit a thin midpiece, absence of the annulus, and disorganization of the mitochondrial sheath. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Colocalizes with alpha-synuclein in Lewy bodies in the substantia nigra pars compacta of Parkinson disease patients. Shows reduced expression in dopaminergic nerve terminals of the striatum in sporadic Parkinson disease. May be defective in GTP-binding.

Similarity. Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. Septin GTPase family.

Isoforms (8)

UniProt ID	Names	Canonical?
O43236-7	7	yes
O43236-1	1, PNUTL2, PNUTL2a, H5/CDCrel-2, SEPT4_i1
O43236-2	2, PNUTL2b, CDCrel-1
O43236-3	3
O43236-4	4
O43236-5	5
O43236-6	ARTS, SEPT4_i2
O43236-8	8

RefSeq proteins (10): NP_001033793, NP_001185642, NP_001243711, NP_001243751, NP_001350732, NP_001355700, NP_001355701, NP_004565, NP_536340, NP_536341 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016491	Septin	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030379	G_SEPTIN_dom	Domain

Pfam: PF00735

UniProt features (38 total): splice variant 9, binding site 5, modified residue 5, region of interest 5, sequence variant 4, sequence conflict 3, compositionally biased region 2, chain 1, domain 1, helix 1, mutagenesis site 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6WB3	X-RAY DIFFRACTION	1.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43236-F1	71.89	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 669–676; 703; 808–816; 866; 881

Post-translational modifications (5): 635, 636, 843, 950, 952

Mutagenesis-validated functional residues (1):

Position	Phenotype
137–139	loss of tgf-beta-induced apoptosis. no translocation to the nucleus following tgf-beta treatment. loss of xiap-binding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-111457	Release of apoptotic factors from the mitochondria
R-HSA-111469	SMAC, XIAP-regulated apoptotic response

MSigDB gene sets: 0 (showing top):

GO Biological Process (15): neuron migration (GO:0001764), apoptotic process (GO:0006915), intracellular protein localization (GO:0008104), regulation of exocytosis (GO:0017157), flagellated sperm motility (GO:0030317), positive regulation of protein ubiquitination (GO:0031398), regulation of apoptotic process (GO:0042981), positive regulation of apoptotic process (GO:0043065), spermatid differentiation (GO:0048515), hematopoietic stem cell homeostasis (GO:0061484), cytoskeleton-dependent cytokinesis (GO:0061640), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), cell division (GO:0051301)

GO Molecular Function (8): magnesium ion binding (GO:0000287), GTPase activity (GO:0003924), structural molecule activity (GO:0005198), GTP binding (GO:0005525), identical protein binding (GO:0042802), molecular adaptor activity (GO:0060090), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (23): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), septin ring (GO:0005940), synaptic vesicle (GO:0008021), microtubule cytoskeleton (GO:0015630), axon (GO:0030424), dendrite (GO:0030425), septin complex (GO:0031105), cell division site (GO:0032153), perikaryon (GO:0043204), sperm annulus (GO:0097227), dopaminergic synapse (GO:0098691), presynapse (GO:0098793), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), transport vesicle (GO:0030133), cytoplasmic vesicle (GO:0031410), motile cilium (GO:0031514), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Apoptotic factor-mediated response	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
apoptotic process	2
developmental process involved in reproduction	2
molecular_function	2
binding	2
intracellular membrane-bounded organelle	2
cytoskeleton	2
cell cortex	2
septin cytoskeleton	2
neuron projection	2
synapse	2
cell migration	1
generation of neurons	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
macromolecule localization	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of programmed cell death	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
spermatogenesis	1
cellular process involved in reproduction in multicellular organism	1
cell differentiation	1
homeostasis of number of cells	1
cytokinesis	1
intrinsic apoptotic signaling pathway	1
positive regulation of intracellular signal transduction	1
positive regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
male gamete generation	1

Protein interactions and networks

STRING

1174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEPTIN4	SEPTIN5	Q99719	937
SEPTIN4	SEPTIN6	Q14141	922
SEPTIN4	SEPTIN8	Q92599	921
SEPTIN4	SEPTIN7	Q16181	920
SEPTIN4	SEPTIN11	Q9NVA2	914
SEPTIN4	ART3	Q13508	863
SEPTIN4	SEPTIN9	Q9UHD8	862
SEPTIN4	SEPTIN3	Q9UH03	860
SEPTIN4	SEPTIN1	Q8WYJ6	826
SEPTIN4	SEPTIN12	Q8IYM1	783
SEPTIN4	XIAP	P98170	781
SEPTIN4	ART1	P52961	764
SEPTIN4	RTKN	Q9BST9	750
SEPTIN4	DNAJB13	P59910	732
SEPTIN4	PRKN	O60260	708

IntAct

50 interactions, top by confidence:

A	B	Type	Score
SEPTIN12	SEPTIN4	psi-mi:“MI:0915”(physical association)	0.730
SEPTIN12	SEPTIN4	psi-mi:“MI:0403”(colocalization)	0.730
SEPTIN12	SEPTIN4	psi-mi:“MI:0914”(association)	0.730
DYNLL1	SEPTIN4	psi-mi:“MI:0915”(physical association)	0.560
SEPTIN4	DYNLL2	psi-mi:“MI:0915”(physical association)	0.560
APP	SEPTIN4	psi-mi:“MI:0915”(physical association)	0.560
SNCA	SEPTIN4	psi-mi:“MI:0915”(physical association)	0.560
HTT	SEPTIN4	psi-mi:“MI:0915”(physical association)	0.560
SEPTIN11	SEPTIN4	psi-mi:“MI:0914”(association)	0.530
SEPTIN7	SEPTIN4	psi-mi:“MI:0914”(association)	0.530
SEPTIN4	SIAH1	psi-mi:“MI:0915”(physical association)	0.400
SEPTIN4	NUDT14	psi-mi:“MI:0915”(physical association)	0.400
SEPTIN4	SEPTIN14	psi-mi:“MI:0915”(physical association)	0.370
SEPTIN4	SEPTIN4	psi-mi:“MI:0915”(physical association)	0.370
SEPTIN4	SEPTIN5	psi-mi:“MI:0915”(physical association)	0.370
SEPTIN4	SEPTIN8	psi-mi:“MI:0915”(physical association)	0.370
SEPTIN4	TSC2	psi-mi:“MI:0915”(physical association)	0.370
SEPTIN4	Caskin1	psi-mi:“MI:0915”(physical association)	0.370
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (59): SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT11 (Co-fractionation), XIAP (Affinity Capture-Western), UBC (Affinity Capture-Western), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS), SEPT4 (Affinity Capture-MS)

ESM2 similar proteins: A0A096MJN4, A2BGU8, A4FUM1, A5D7Q3, A5PJU9, A6QQL3, B0BNF1, B0KWP7, B1H120, B1MTN8, B2KIE9, B3GNI6, B5FW69, O36023, O43236, P28661, P32468, P40797, P42209, P48010, Q08DM7, Q0VC68, Q0VCP4, Q14141, Q2KJB1, Q3SZN0, Q4R4X5, Q4R555, Q4V8G5, Q5EB96, Q5PQK1, Q5R6R7, Q5REG8, Q6AXA6, Q6IRQ5, Q8C1B7, Q8C650, Q8CHH9, Q8IYM1, Q92599

Diamond homologs: A0A096MJN4, A0A3Q0KDV9, A1L0Y5, A2BGU8, A2VE99, A4FUM1, A5D7Q3, A5PJU9, A6QQL3, B0BNF1, B0KWP7, B1H120, B1MTN8, B2KIE9, B3GNI6, B5FW69, G1UB61, O36023, O43236, O55131, O60165, P25342, P28661, P32457, P32458, P32468, P39826, P39827, P40797, P41901, P42207, P42208, P42209, P48008, P48009, P48010, P54359, Q04921, Q08DM7, Q09116

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
AREL1	“down-regulates quantity by destabilization”	SEPTIN4	ubiquitination
PRKN	“down-regulates quantity by destabilization”	SEPTIN4	ubiquitination
XIAP	“down-regulates quantity”	SEPTIN4	ubiquitination
SEPTIN4	“down-regulates quantity”	XIAP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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.

GO biological processes:

GO term	Partners	Fold	FDR
cytoskeleton-dependent cytokinesis	11	339.5×	1e-24
intracellular protein localization	12	48.3×	7e-16
spermatogenesis	6	8.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	77
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3897908	R241*	Pathogenic
3897909	R69*	Pathogenic
253345	GRCh37/hg19 17q22(chr17:55916829-56770618)x1	Likely pathogenic

SpliceAI

2607 predictions. Top by Δscore:

Variant	Effect	Δscore
17:58520737:TCTCA:T	donor_loss	1.0000
17:58520738:CTCA:C	donor_loss	1.0000
17:58520740:CACCT:C	donor_loss	1.0000
17:58520741:A:T	donor_loss	1.0000
17:58520741:ACCT:A	donor_gain	1.0000
17:58520742:CCTC:C	donor_gain	1.0000
17:58520744:T:TA	donor_gain	1.0000
17:58520750:T:C	donor_gain	1.0000
17:58520836:CAGTT:C	acceptor_gain	1.0000
17:58520838:GTTTG:G	acceptor_gain	1.0000
17:58520839:TTTG:T	acceptor_gain	1.0000
17:58520840:T:TC	acceptor_gain	1.0000
17:58520840:TTGC:T	acceptor_loss	1.0000
17:58520841:TG:T	acceptor_gain	1.0000
17:58520842:GCTAA:G	acceptor_loss	1.0000
17:58520843:C:CC	acceptor_gain	1.0000
17:58520940:A:AC	donor_gain	1.0000
17:58520940:AC:A	donor_gain	1.0000
17:58520941:C:CC	donor_gain	1.0000
17:58520941:CC:C	donor_gain	1.0000
17:58520979:T:TA	donor_gain	1.0000
17:58520996:A:AC	donor_gain	1.0000
17:58520997:C:CC	donor_gain	1.0000
17:58521161:C:CC	acceptor_gain	1.0000
17:58521558:T:TA	donor_gain	1.0000
17:58521728:T:TA	donor_gain	1.0000
17:58521729:C:A	donor_gain	1.0000
17:58521731:CTCA:C	donor_loss	1.0000
17:58521732:TCAC:T	donor_loss	1.0000
17:58521733:CACT:C	donor_loss	1.0000

AlphaMissense

6477 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:58521091:A:G	L395P	1.000
17:58521267:C:A	W367C	1.000
17:58521267:C:G	W367C	1.000
17:58521269:A:G	W367R	1.000
17:58521269:A:T	W367R	1.000
17:58521283:C:T	G362D	1.000
17:58521325:C:T	G348D	1.000
17:58521340:G:T	P343Q	1.000
17:58522016:C:G	D250H	1.000
17:58525129:A:G	L204P	1.000
17:58525135:A:G	L202P	1.000
17:58525738:G:C	F165L	1.000
17:58525738:G:T	F165L	1.000
17:58525740:A:G	F165L	1.000
17:58525754:A:G	L160P	1.000
17:58525763:T:A	K157I	1.000
17:58525766:C:T	G156D	1.000
17:58526242:A:C	F143L	1.000
17:58526242:A:T	F143L	1.000
17:58526244:A:G	F143L	1.000
17:58526264:C:G	R136P	1.000
17:58526282:A:G	L130P	1.000
17:58526282:A:T	L130H	1.000
17:58526290:A:C	F127L	1.000
17:58526290:A:T	F127L	1.000
17:58526291:A:C	F127C	1.000
17:58526291:A:G	F127S	1.000
17:58526292:A:G	F127L	1.000
17:58526294:C:T	G126D	1.000
17:58526295:C:G	G126R	1.000

dbSNP variants (sampled 300 via entrez): RS1000139594 (17:58520344 C>A), RS1000191272 (17:58537951 G>A), RS1000222330 (17:58544766 C>A), RS1000291718 (17:58534283 T>G), RS1000412296 (17:58533889 A>G), RS1000495418 (17:58540829 A>G,T), RS1000941971 (17:58528199 T>C,G), RS1001406580 (17:58546121 G>A), RS1001612826 (17:58525302 C>G), RS1001899639 (17:58533756 C>T), RS1001968142 (17:58532443 C>A), RS1001976149 (17:58540530 C>A), RS1002016903 (17:58526010 G>T), RS1002225567 (17:58541683 A>G,T), RS1002472424 (17:58525666 T>C)

Disease associations

OMIM: gene MIM:603696 | disease phenotypes: MIM:613390, MIM:621194

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility	Strong	Autosomal recessive

Mondo (3): Fanconi anemia complementation group O (MONDO:0013248), spermatogenic failure 99 (MONDO:0978297), male infertility (MONDO:0005372)

Orphanet (1): Fanconi anemia (Orphanet:84)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002023_1	Testicular germ cell tumor	4.000000e-13
GCST002774_29	Cognitive function	3.000000e-07
GCST006073_13	Tenofovir clearance in HIV infection	1.000000e-07
GCST006291_88	Spherical equivalent or myopia (age of diagnosis)	3.000000e-09
GCST90002391_95	Mean corpuscular hemoglobin concentration	6.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004847	age at onset
EFO:0004528	mean corpuscular hemoglobin concentration

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	7
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	3
Cocaine	decreases expression	3
Air Pollutants	increases oxidation, decreases expression, affects cotreatment, increases abundance	2
Cadmium	increases abundance, decreases expression	2
Cisplatin	increases expression, affects expression, affects cotreatment	2
Oxygen	increases expression, increases reaction, decreases reaction	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
heclin	decreases reaction, increases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	affects cotreatment, decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
butyraldehyde	increases expression	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
pentanal	increases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	1
dorsomorphin	increases expression, affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT01304927	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial
NCT02349945	PHASE2/PHASE3	COMPLETED	FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
NCT05222841	PHASE2/PHASE3	COMPLETED	The Effectiveness of Spermotrend Food Supplement in the Treatment of Male Infertility
NCT05616598	PHASE2/PHASE3	COMPLETED	Effect of New Oral Treatment for Hepatitis C Virus on Seminal Parameters
NCT02025270	PHASE1/PHASE2	COMPLETED	MSCs For Treatment of Azoospermic Patients
NCT04541459	EARLY_PHASE1	UNKNOWN	Validation of New Devices Against Ambient Electromagnetic Radiation
NCT05792813	EARLY_PHASE1	UNKNOWN	Efficacy and Safety of Linggui Yangyuan Paste in Patients With Male Infertility
NCT06188936	EARLY_PHASE1	COMPLETED	Home Semen Analysis Tests As a Screening Tool for Fertility Patients
NCT00012480	Not specified	COMPLETED	Effect of Environmental Exposures on the Egg Fertilizing Ability of Human Sperm
NCT00044369	Not specified	COMPLETED	Role of the Toxic Metal Cadmium in the Mechanism Producing Infertility With a Varicocele
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists
NCT00178516	Not specified	COMPLETED	Vitamin E and Male Infertility
NCT00315029	Not specified	COMPLETED	Patient-Centered Implementation Trial for Single Embryo Transfer
NCT00341120	Not specified	COMPLETED	Genetic Causes of Male Infertility
NCT00481403	Not specified	COMPLETED	Study of Sperm Molecular Factors Implicated in Male Fertility
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT00596739	Not specified	COMPLETED	A Study of the Pre- and Post-operative Semen Analyses and Reproductive Hormone Levels of Men Undergoing Weight-reduction Surgery
NCT00756561	Not specified	COMPLETED	HOP-2A - Intratesticular Hormone Levels
NCT00961558	Not specified	TERMINATED	Canadian Varicocelectomy Initiative (CVI): Effects on Male Fertility and Testicular Function of Varicocelectomy
NCT01075334	Not specified	UNKNOWN	Is a Carnitine Based Food Supplement (PorimoreTM) for Infertile Men Superior to Folate and Zinc With Regard to Pregnancy Rates in Intrauterine Insemination Cycles?
NCT01178463	Not specified	UNKNOWN	Spermatogonial Stem Cells in Azoospermic Patients: a Comparison Between Obstructive and Non-obstructive Azoospermia