SPAG4

Summary

SPAG4 (sperm associated antigen 4, HGNC:11214) is a protein-coding gene on chromosome 20q11.22, encoding Sperm-associated antigen 4 protein (Q9NPE6). Involved in spermatogenesis.

The mammalian sperm flagellum contains two cytoskeletal structures associated with the axoneme: the outer dense fibers surrounding the axoneme in the midpiece and principal piece and the fibrous sheath surrounding the outer dense fibers in the principal piece of the tail. Defects in these structures are associated with abnormal tail morphology, reduced sperm motility, and infertility. In the rat, the protein encoded by this gene associates with an outer dense fiber protein via a leucine zipper motif and localizes to the microtubules of the manchette and axoneme during sperm tail development. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 6676 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 46 total
• MANE Select transcript: NM_003116

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11214
Approved symbol	SPAG4
Name	sperm associated antigen 4
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	SUN4, CT127
Ensembl gene	ENSG00000061656
Ensembl biotype	protein_coding
OMIM	603038
Entrez	6676

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000374273, ENST00000430878, ENST00000454819, ENST00000462896, ENST00000463973, ENST00000468248, ENST00000498203, ENST00000679710, ENST00000861575, ENST00000957539

RefSeq mRNA: 2 — MANE Select: NM_003116 NM_001317931, NM_003116

CCDS: CCDS13259, CCDS93032

Canonical transcript exons

ENST00000374273 — 12 exons

Exon	Start	End
ENSE00000661664	35617136	35617240
ENSE00000661668	35618612	35618720
ENSE00001462991	35615829	35616307
ENSE00003460654	35617520	35617586
ENSE00003509639	35618087	35618130
ENSE00003514447	35618923	35618998
ENSE00003543101	35619579	35619746
ENSE00003544571	35619195	35619310
ENSE00003550634	35618450	35618475
ENSE00003555690	35617779	35617840
ENSE00003556755	35620684	35620773
ENSE00003891747	35620876	35621094

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 96.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.9955 / max 59.7410, expressed in 1320 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184313	2.3319	1016
184311	0.6065	278
184314	0.5075	229
184315	0.4345	195
184312	0.1152	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	96.26	gold quality
right testis	UBERON:0004534	93.87	gold quality
left testis	UBERON:0004533	93.68	gold quality
testis	UBERON:0000473	90.83	gold quality
pancreas	UBERON:0001264	86.58	gold quality
adenohypophysis	UBERON:0002196	85.34	gold quality
left ovary	UBERON:0002119	85.19	gold quality
right ovary	UBERON:0002118	84.30	gold quality
left uterine tube	UBERON:0001303	84.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.79	gold quality
spleen	UBERON:0002106	83.16	gold quality
pituitary gland	UBERON:0000007	82.96	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.95	gold quality
transverse colon	UBERON:0001157	81.45	gold quality
right adrenal gland cortex	UBERON:0035827	81.40	gold quality
lower esophagus mucosa	UBERON:0035834	81.37	gold quality
body of stomach	UBERON:0001161	81.06	gold quality
endocervix	UBERON:0000458	80.98	gold quality
left adrenal gland cortex	UBERON:0035825	80.86	gold quality
minor salivary gland	UBERON:0001830	80.56	gold quality
right adrenal gland	UBERON:0001233	80.05	gold quality
adrenal tissue	UBERON:0018303	80.04	gold quality
stromal cell of endometrium	CL:0002255	79.98	gold quality
bone marrow cell	CL:0002092	79.73	gold quality
left adrenal gland	UBERON:0001234	79.51	gold quality
small intestine	UBERON:0002108	79.38	gold quality
mucosa of transverse colon	UBERON:0004991	79.11	gold quality
ovary	UBERON:0000992	78.78	gold quality
gall bladder	UBERON:0002110	78.60	gold quality
apex of heart	UBERON:0002098	78.49	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	107.84
E-HCAD-4	yes	39.46
E-ANND-3	yes	34.19
E-MTAB-8410	yes	32.41
E-CURD-46	yes	31.72
E-HCAD-11	yes	20.16
E-MTAB-10553	yes	11.02
E-HCAD-1	yes	10.45
E-MTAB-6108	no	223.43

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 6)

• SPAG4 is an independent prognostic factor in renal cell carcinoma and plays a crucial role in cytokinesis to defend against hypoxia-induced tetraploid formation. (PMID:23602831)
• SPAG4 knockdown reduces the invasion capability of RCC cells. (PMID:23818324)
• SPAG4, in cooperation with Nesprin3, has a fundamental pathological function in the migration of lung carcinoma cells. (PMID:29901114)
• Our study revealed that SPAG4 was identified as a cancer biomarker for glioblastoma and might be a promising target for clinical diagnosis and intervention of glioblastoma. (PMID:30817682)
• Results indicate that sperm associated antigen 4 (SPAG4L/SPAG4Lbeta) transcript isoform interacts with spectrin repeat containing nuclear envelope protein 2 (Nesprin2) in the meiotic process. (PMID:31144711)
• Human sperm-associated antigen 4 as a potential prognostic biomarker of lung squamous cell carcinoma. (PMID:34311595)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spag4	ENSMUSG00000038180
rattus_norvegicus	Spag4	ENSRNOG00000048056
caenorhabditis_elegans		WBGENE00006816

Paralogs (4): SUN2 (ENSG00000100242), SUN3 (ENSG00000164744), SUN1 (ENSG00000164828), SUN5 (ENSG00000167098)

Protein

Protein identifiers

Sperm-associated antigen 4 protein — Q9NPE6 (reviewed: Q9NPE6)

Alternative names: Outer dense fiber-associated protein SPAG4, SUN domain-containing protein 4

All UniProt accessions (4): Q9NPE6, A0A7P0Z4G5, C9JJZ6, Q5JX49

UniProt curated annotations — full annotation on UniProt →

Function. Involved in spermatogenesis. Required for sperm head formation but not required to establish and maintain general polarity of the sperm head. Required for anchoring and organization of the manchette. Required for targeting of SUN3 and probably SYNE1 through a probable SUN1:SYNE3 LINC complex to the nuclear envelope and involved in accurate posterior sperm head localization of the complex. May anchor SUN3 the nuclear envelope. Involved in maintenance of the nuclear envelope integrity. May assist the organization and assembly of outer dense fibers (ODFs), a specific structure of the sperm tail.

Subunit / interactions. Homodimer. Interacts with ODF1. May associate with microtubules. Interacts with SUN3 and SYNE1; suggesting the formation of a spermatogenesis-specific LINC complex; a SUN domain-based heterotrimer with SUN3 may associate with SYNE1. Interacts with SEPT12 and LMNB1; during spermatogenesis.

Subcellular location. Membrane. Cytoplasm. Cytoskeleton. Flagellum axoneme. Nucleus envelope. Nucleus inner membrane.

Tissue specificity. Predominantly epressed in testis. Expressed in ejaculated spermatozoa (at protein level).

RefSeq proteins (2): NP_001304860, NP_003107* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012919	SUN_dom	Domain
IPR045119	SUN1-5	Family

Pfam: PF07738

UniProt features (9 total): compositionally biased region 3, transmembrane region 2, chain 1, domain 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPE6-F1	71.79	0.38

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, GOZGIT_ESR1_TARGETS_DN, MENSE_HYPOXIA_UP, GOBP_MALE_GAMETE_GENERATION, LIAO_METASTASIS, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, HAN_SATB1_TARGETS_DN, chr20q11, GOCC_NUCLEAR_ENVELOPE, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_NUCLEAR_INNER_MEMBRANE, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_NUCLEAR_MEMBRANE, ZHAN_MULTIPLE_MYELOMA_CD2_UP, GOMF_STRUCTURAL_MOLECULE_ACTIVITY

GO Biological Process (2): spermatogenesis (GO:0007283), cell differentiation (GO:0030154)

GO Molecular Function (3): structural molecule activity (GO:0005198), protein-membrane adaptor activity (GO:0043495), protein binding (GO:0005515)

GO Cellular Component (10): nuclear envelope (GO:0005635), nuclear inner membrane (GO:0005637), cytoskeleton (GO:0005856), meiotic nuclear membrane microtubule tethering complex (GO:0034993), nucleus (GO:0005634), cytoplasm (GO:0005737), cilium (GO:0005929), membrane (GO:0016020), motile cilium (GO:0031514), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
molecular_function	1
protein-macromolecule adaptor activity	1
binding	1
nucleus	1
endomembrane system	1
organelle envelope	1
organelle inner membrane	1
nuclear membrane	1
intracellular membraneless organelle	1
microtubule organizing center attachment site	1
nuclear membrane microtubule tethering complex	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

1212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAG4	ODF1	Q14990	998
SPAG4	SPAG5	Q96R06	737
SPAG4	SYNE1	Q8NF91	737
SPAG4	SYNE3	Q6ZMZ3	636
SPAG4	SYNE4	Q8N205	587
SPAG4	SEPTIN12	Q8IYM1	543
SPAG4	SYNE2	Q8WXH0	532
SPAG4	KASH5	Q8N6L0	530
SPAG4	SEPTIN1	Q8WYJ6	475
SPAG4	SEPTIN6	Q14141	471
SPAG4	EMD	P50402	447
SPAG4	HOOK1	Q9UJC3	443
SPAG4	TOR3A	Q9H497	442
SPAG4	MRPS18A	Q9NVS2	441
SPAG4	OTOR	Q9NRC9	439

IntAct

88 interactions, top by confidence:

A	B	Type	Score
SEPTIN12	SPAG4	psi-mi:“MI:0915”(physical association)	0.610
SPAG4	SEPTIN12	psi-mi:“MI:0915”(physical association)	0.610
SEPTIN12	SPAG4	psi-mi:“MI:0403”(colocalization)	0.610
TMEM120A	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
ZDHHC24	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
CYP4F2	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
ABHD16A	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
TMEM60	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
PGA4	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
GOSR2	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
ASGR1	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
TSPO2	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
MS4A13	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
TMEM187	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
PTPN9	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
BMP10	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
TNMD	SPAG4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (31): SPAG4 (Two-hybrid), SCD (Two-hybrid), ERMP1 (Two-hybrid), GOSR2 (Two-hybrid), TSPO2 (Two-hybrid), IGFBP5 (Two-hybrid), SEC22A (Two-hybrid), TMEM60 (Two-hybrid), NRM (Two-hybrid), C16orf58 (Two-hybrid), ASGR1 (Two-hybrid), CSGALNACT1 (Two-hybrid), BMP10 (Two-hybrid), SUN5 (Two-hybrid), PTPN9 (Two-hybrid)

ESM2 similar proteins: A1L3T7, A2CI98, A2CJ06, A2VCK2, D3ZQL6, E1BBG2, M3WHG5, O15037, O43918, O70303, O75333, P48778, P59729, Q32PJ7, Q3KP66, Q3T191, Q5JYT7, Q5T124, Q5U4F0, Q5XIS1, Q6AXX1, Q6VYH9, Q7TSI1, Q80U38, Q8BGT6, Q8BHW9, Q8BWG4, Q8BWQ5, Q8BZ33, Q8BZW2, Q8C0J6, Q8C2K5, Q8CFK6, Q8IV53, Q8IY33, Q8IZW8, Q8K1S6, Q8K330, Q8N3F8, Q8TB24

Diamond homologs: A0A0B4KEE4, O55034, O94901, Q09825, Q0II64, Q20745, Q5SS91, Q8BJS4, Q8TAQ9, Q8TC36, Q95LV7, Q9D666, Q9DA32, Q9JJF2, Q9NPE6, Q9UH99, Q9SG79, Q558Z2, Q9FF75

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SPAG4	“form complex”	“LINC complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1760 predictions. Top by Δscore:

Variant	Effect	Δscore
20:35618611:GTGA:G	acceptor_gain	1.0000
20:35619193:A:AG	acceptor_gain	1.0000
20:35619194:G:GG	acceptor_gain	1.0000
20:35619307:GGAG:G	donor_gain	1.0000
20:35619308:GAG:G	donor_gain	1.0000
20:35619308:GAGG:G	donor_gain	1.0000
20:35619309:AGGT:A	donor_loss	1.0000
20:35619310:GGTG:G	donor_loss	1.0000
20:35619311:G:C	donor_loss	1.0000
20:35620679:ACCAG:A	acceptor_gain	1.0000
20:35620680:CCA:C	acceptor_loss	1.0000
20:35620681:CA:C	acceptor_loss	1.0000
20:35620682:A:AG	acceptor_gain	1.0000
20:35620683:G:GG	acceptor_gain	1.0000
20:35620683:G:GT	acceptor_loss	1.0000
20:35616224:G:GT	donor_gain	0.9900
20:35618085:A:AG	acceptor_gain	0.9900
20:35618086:G:GG	acceptor_gain	0.9900
20:35618086:GC:G	acceptor_gain	0.9900
20:35618131:G:GG	donor_gain	0.9900
20:35618610:A:AG	acceptor_gain	0.9900
20:35618611:G:GG	acceptor_gain	0.9900
20:35618611:GT:G	acceptor_gain	0.9900
20:35619039:A:T	donor_gain	0.9900
20:35619189:TTCCA:T	acceptor_loss	0.9900
20:35619192:CA:C	acceptor_loss	0.9900
20:35619193:A:AC	acceptor_loss	0.9900
20:35619194:GGA:G	acceptor_gain	0.9900
20:35619306:TGGAG:T	donor_gain	0.9900
20:35619307:GGAGG:G	donor_gain	0.9900

AlphaMissense

2828 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:35619605:G:C	W312C	0.997
20:35619605:G:T	W312C	0.997
20:35620762:T:C	F386L	0.997
20:35620764:C:A	F386L	0.997
20:35620764:C:G	F386L	0.997
20:35620726:T:C	F374L	0.996
20:35620728:C:A	F374L	0.996
20:35620728:C:G	F374L	0.996
20:35619603:T:A	W312R	0.994
20:35619603:T:C	W312R	0.994
20:35620910:T:C	I401T	0.994
20:35619637:T:C	I323T	0.993
20:35620732:T:C	F376L	0.993
20:35620734:C:A	F376L	0.993
20:35620734:C:G	F376L	0.993
20:35619610:T:G	F314C	0.991
20:35620916:T:C	I403T	0.991
20:35620942:T:C	F412L	0.991
20:35620944:C:A	F412L	0.991
20:35620944:C:G	F412L	0.991
20:35620964:G:C	R419P	0.991
20:35619637:T:A	I323N	0.990
20:35620894:T:C	F396L	0.990
20:35620896:T:A	F396L	0.990
20:35620896:T:G	F396L	0.990
20:35619610:T:C	F314S	0.989
20:35620910:T:G	I401S	0.989
20:35620926:C:A	N406K	0.989
20:35620926:C:G	N406K	0.989
20:35620961:T:A	V418D	0.989

dbSNP variants (sampled 300 via entrez): RS1000461465 (20:35617942 C>T), RS1001009870 (20:35619406 G>A,T), RS1001093449 (20:35616488 A>G), RS1001619666 (20:35620096 G>A), RS1001634950 (20:35617450 G>T), RS1002904029 (20:35616105 C>T), RS1003281922 (20:35616379 G>A,C), RS1003293841 (20:35621304 T>C), RS1003429631 (20:35621117 A>T), RS1004081884 (20:35615727 C>A), RS1004184895 (20:35614125 C>T), RS1005606698 (20:35619131 GCCCCCGCGCCCCGACT>G), RS1006149514 (20:35620281 T>A), RS1006323140 (20:35620532 C>T), RS1006518851 (20:35618745 C>A,G,T)

Disease associations

OMIM: gene MIM:603038 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005956_31	Waist-to-hip ratio adjusted for BMI	8.000000e-08
GCST005958_16	Waist-to-hip ratio adjusted for BMI (age >50)	6.000000e-06
GCST005962_40	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-08
GCST010002_66	Refractive error	2.000000e-20
GCST010703_112	Brain morphology (MOSTest)	4.000000e-19

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
bisphenol S	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	increases methylation, affects expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chloride	increases expression, decreases reaction	1
cobaltous chloride	increases expression, decreases reaction	1
nickel chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Benzene	increases expression	1
Carbamazepine	affects expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	increases expression, affects cotreatment	1
Oxygen	increases expression	1
Quercetin	affects expression	1

Clinical trials (associated diseases)

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