SPAG6

Summary

SPAG6 (sperm associated antigen 6, HGNC:11215) is a protein-coding gene on chromosome 10p12.2, encoding Sperm-associated antigen 6 (O75602). Important for structural integrity of the central apparatus in the sperm tail and for flagellar motility.

The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein expressed by this gene is recognized by anti-sperm antibodies from an infertile man. This protein localizes to the tail of permeabilized human sperm and contains eight contiguous armadillo repeats, a motif known to mediate protein-protein interactions. Studies in mice suggest that this protein is involved in sperm flagellar motility and maintenance of the structural integrity of mature sperm. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9576 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 72 total
• MANE Select transcript: NM_012443

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11215
Approved symbol	SPAG6
Name	sperm associated antigen 6
Location	10p12.2
Locus type	gene with protein product
Status	Approved
Aliases	Repro-SA-1, PF16, CT141, FAP194, CFAP194
Ensembl gene	ENSG00000077327
Ensembl biotype	protein_coding
OMIM	605730
Entrez	9576

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000313311, ENST00000376603, ENST00000376624, ENST00000435326, ENST00000456231, ENST00000487973, ENST00000488555, ENST00000490361, ENST00000538630, ENST00000853262, ENST00000853263, ENST00000853264, ENST00000853265, ENST00000853266

RefSeq mRNA: 4 — MANE Select: NM_012443 NM_001253854, NM_001253855, NM_012443, NM_172242

CCDS: CCDS58071, CCDS7139, CCDS7140, CCDS73072

Canonical transcript exons

ENST00000376624 — 11 exons

Exon	Start	End
ENSE00000694057	22386754	22386959
ENSE00000694059	22387823	22387996
ENSE00000694062	22389160	22389312
ENSE00000996547	22368495	22368678
ENSE00000996548	22364853	22365019
ENSE00001843576	22416619	22417610
ENSE00003271833	22411031	22411176
ENSE00003472069	22345723	22345818
ENSE00003570565	22401161	22401277
ENSE00003639381	22391729	22391920
ENSE00003685007	22345496	22345636

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 99.20.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7412 / max 288.2433, expressed in 353 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104252	1.5204	299
104257	0.2209	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.20	gold quality
epithelium of bronchus	UBERON:0002031	98.70	gold quality
right uterine tube	UBERON:0001302	98.19	gold quality
bronchus	UBERON:0002185	98.07	gold quality
sperm	CL:0000019	96.69	gold quality
male germ cell	CL:0000015	96.13	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.94	gold quality
choroid plexus epithelium	UBERON:0003911	95.72	gold quality
left testis	UBERON:0004533	95.39	gold quality
right testis	UBERON:0004534	95.25	gold quality
adult organism	UBERON:0007023	93.48	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.40	gold quality
testis	UBERON:0000473	92.78	gold quality
epithelium of nasopharynx	UBERON:0001951	88.97	gold quality
nasal cavity epithelium	UBERON:0005384	88.66	gold quality
secondary oocyte	CL:0000655	87.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.78	gold quality
oocyte	CL:0000023	84.69	gold quality
pituitary gland	UBERON:0000007	84.13	gold quality
adenohypophysis	UBERON:0002196	83.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.43	gold quality
nasal cavity mucosa	UBERON:0001826	79.82	gold quality
trachea	UBERON:0003126	78.88	gold quality
caput epididymis	UBERON:0004358	78.53	gold quality
fallopian tube	UBERON:0003889	74.73	gold quality
islet of Langerhans	UBERON:0000006	74.42	gold quality
right lung	UBERON:0002167	74.41	gold quality
oviduct epithelium	UBERON:0004804	68.93	gold quality
hypothalamus	UBERON:0001898	68.84	gold quality
corpus callosum	UBERON:0002336	68.34	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	61.23
E-HCAD-1	yes	25.59
E-MTAB-9388	yes	6.76
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXJ1, SOX5

miRNA regulators (miRDB)

51 targeting SPAG6, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-10399-5P	99.17	69.87	2610

Literature-anchored findings (GeneRIF, showing 14)

• Data describe the cloning of human and mouse Pf20 proteins that interact with Spag6 protein. (PMID:12391165)
• SPAG6 is a S-SOX5 target gene, indicating a key role for S-SOX5 in the formation and function of motile cilia. (PMID:20668334)
• studies demonstrate a role for Spag6 in the pathogenesis of OM in mice, possibly through its role in the regulation of cilia/basal body polarity through the PCP-dependent mechanisms in the middle ear and Eustachian tubes. (PMID:25393619)
• These findings demonstrate that SPAG6 might have a role in malignant myeloid hematologic cell proliferation and apoptosis by regulating caspase proteins and p53, suggesting that SPAG6 may be a potential therapeutic target. (PMID:25405588)
• SPAG6 and L1TD1 are tumor-specifically methylated in NSCLCs and that DNA methylation is involved in the transcriptional regulation of these genes. Moreover, in vitro as well as in vivo experiments revealed tumor-cell growth suppressing properties of L1TD1 in NSCLC cells. (PMID:28093071)
• Study demonstrates that SPAG6 may regulate apoptosis through the TRAIL signal pathway by inhibiting the expression of FADD and the interactions between FADD and the TRAIL death receptors. (PMID:28393201)
• These results demonstrate that SPAG6 silencing induces PTEN expression to regulate apoptosis though the PI3K/AKT pathway, indicating that SPAG6 may be a potential therapeutic target for myelodysplastic syndromes. (PMID:29749435)
• Upregulation of SPAG6 is associated with Myelodysplastic Syndrome. (PMID:30835546)
• Patients with severe asthenoteratospermia carrying SPAG6 or RSPH3 mutations have a positive pregnancy outcome following intracytoplasmic sperm injection. (PMID:32124190)
• SPAG6 promotes cell proliferation and inhibits apoptosis through the PTEN/PI3K/AKT pathway in Burkitt lymphoma. (PMID:33000212)
• Measurable Residual Disease Monitoring of SPAG6, ST18, PRAME, and XAGE1A Expression in Peripheral Blood May Detect Imminent Relapse in Childhood Acute Myeloid Leukemia. (PMID:34600138)
• Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF. (PMID:35232447)
• Upregulated SPAG6 promotes acute myeloid leukemia progression through MYO1D that regulates the EGFR family expression. (PMID:35667090)
• SPAG6 regulates cell proliferation and apoptosis via TGF-beta/Smad signal pathway in adult B-cell acute lymphoblastic leukemia. (PMID:38147275)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spag6	ENSDARG00000020158
mus_musculus	Spag6l	ENSMUSG00000022783
mus_musculus	Spag6	ENSMUSG00000037708
rattus_norvegicus	Spag6	ENSRNOG00000022021
rattus_norvegicus	Spag6l	ENSRNOG00000025787

Protein

Protein identifiers

Sperm-associated antigen 6 — O75602 (reviewed: O75602)

Alternative names: Protein PF16 homolog, Repro-SA-1, Sperm flagellar protein

All UniProt accessions (5): O75602, A0A0A0MRT8, A0A0A0MSY0, A0A0A0MT17, A0A140VJU9

UniProt curated annotations — full annotation on UniProt →

Function. Important for structural integrity of the central apparatus in the sperm tail and for flagellar motility.

Subunit / interactions. Interacts with SPAG16 and SPAG17.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Cilium. Flagellum. Cilium axoneme.

Tissue specificity. Highly expressed in testis.

Isoforms (5)

UniProt ID	Names	Canonical?
O75602-1	1	yes
O75602-2	2
O75602-3	3
O75602-4	4
O75602-5	5

RefSeq proteins (4): NP_001240783, NP_001240784, NP_036575, NP_758442 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily

Pfam: PF00514

UniProt features (20 total): repeat 8, splice variant 5, sequence conflict 4, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75602-F1	95.13	0.89

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 154 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEURON_PROJECTION_EXTENSION, GOCC_SECRETORY_GRANULE, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_MALE_GAMETE_GENERATION, CAGCTG_AP4_Q5, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, HEN1_01, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY

GO Biological Process (5): epithelial cilium movement involved in extracellular fluid movement (GO:0003351), sperm axoneme assembly (GO:0007288), filopodium assembly (GO:0046847), neuron projection extension (GO:1990138), cell projection organization (GO:0030030)

GO Molecular Function (2): microtubule binding (GO:0008017), protein binding (GO:0005515)

GO Cellular Component (12): acrosomal vesicle (GO:0001669), extracellular region (GO:0005576), nucleus (GO:0005634), microtubule (GO:0005874), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), sperm principal piece (GO:0097228), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), motile cilium (GO:0031514), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeleton	2
cilium movement	1
extracellular transport	1
microtubule-based transport	1
developmental process involved in reproduction	1
axoneme assembly	1
sperm flagellum assembly	1
plasma membrane bounded cell projection assembly	1
developmental cell growth	1
neuron projection morphogenesis	1
developmental growth involved in morphogenesis	1
cellular component organization	1
tubulin binding	1
binding	1
secretory granule	1
intracellular membrane-bounded organelle	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
microtubule	1
ciliary plasm	1
sperm flagellum	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

2184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAG6	SPAG16	Q8N0X2	990
SPAG6	MEIG1	Q5JSS6	966
SPAG6	SPAG17	Q6Q759	886
SPAG6	SPEF2	Q9C093	739
SPAG6	CFAP221	Q4G0U5	736
SPAG6	C1D	Q13901	621
SPAG6	HYDIN	Q4G0P3	611
SPAG6	SPEF1	Q9Y4P9	596
SPAG6	DRC4	O95995	595
SPAG6	DNAH9	Q9NYC9	591
SPAG6	SPATA17	Q96L03	589
SPAG6	DNAI1	Q9UI46	587
SPAG6	DLEC1	Q9Y238	578
SPAG6	IFT20	Q8IY31	578
SPAG6	DPY30	Q9C005	575

IntAct

6 interactions, top by confidence:

A	B	Type	Score
SPAG6	GAPDH	psi-mi:“MI:0915”(physical association)	0.400
KDM5C	SPAG6	psi-mi:“MI:0914”(association)	0.350
C4BPA	SPAG6	psi-mi:“MI:0914”(association)	0.350
SPAG6	MT-ND1	psi-mi:“MI:0914”(association)	0.350
SGIP1	SPAG6	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): ABCF1 (Co-fractionation), GAPDH (Proximity Label-MS), SPAG6 (Negative Genetic), OCIAD1 (Affinity Capture-MS), TMEM242 (Affinity Capture-MS), PTPLB (Affinity Capture-MS), SPAG6 (Affinity Capture-MS), NT5C3A (Affinity Capture-MS), ND1 (Affinity Capture-MS), TVP23C (Affinity Capture-MS), KIAA1919 (Affinity Capture-MS), PCYOX1 (Affinity Capture-MS), SLC20A2 (Affinity Capture-MS), PXMP2 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS)

ESM2 similar proteins: A2AU72, B0F9L4, E9Q912, F1QWA8, O35099, O46563, O75165, O75602, O93614, P0C6R2, P39968, P42345, P42346, P52306, Q04173, Q1RMS6, Q21029, Q5EFZ4, Q5PPZ9, Q5W041, Q5ZL91, Q66L58, Q68FK4, Q6BTZ4, Q6C5Y8, Q6CX49, Q6DD21, Q6FJV1, Q6NUP7, Q6PIY5, Q757R0, Q7YRF1, Q80TR8, Q80W92, Q80WQ2, Q84ZC0, Q8BVE3, Q8BW49, Q8C0Y0, Q8NFP9

Diamond homologs: O75602, Q9JLI7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOXJ1	“up-regulates quantity by expression”	SPAG6	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2721 predictions. Top by Δscore:

Variant	Effect	Δscore
10:22364839:A:AG	acceptor_gain	1.0000
10:22364840:T:G	acceptor_gain	1.0000
10:22364841:A:AG	acceptor_gain	1.0000
10:22364842:A:G	acceptor_gain	1.0000
10:22364846:A:AG	acceptor_gain	1.0000
10:22364852:GGTGT:G	acceptor_gain	1.0000
10:22364867:CTG:C	acceptor_gain	1.0000
10:22365016:GAAT:G	donor_gain	1.0000
10:22365019:TGTA:T	donor_loss	1.0000
10:22365020:G:C	donor_loss	1.0000
10:22365020:G:GG	donor_gain	1.0000
10:22365021:T:G	donor_loss	1.0000
10:22368493:A:AG	acceptor_gain	1.0000
10:22368494:G:GA	acceptor_gain	1.0000
10:22368494:GC:G	acceptor_gain	1.0000
10:22391720:AC:A	acceptor_gain	1.0000
10:22391721:C:CA	acceptor_gain	1.0000
10:22391724:T:A	acceptor_gain	1.0000
10:22391724:TGCA:T	acceptor_loss	1.0000
10:22391725:GCAG:G	acceptor_loss	1.0000
10:22391727:A:AG	acceptor_gain	1.0000
10:22391727:AG:A	acceptor_gain	1.0000
10:22391727:AGG:A	acceptor_gain	1.0000
10:22391727:AGGGT:A	acceptor_gain	1.0000
10:22391728:G:A	acceptor_loss	1.0000
10:22391728:G:GG	acceptor_gain	1.0000
10:22391728:GG:G	acceptor_gain	1.0000
10:22391728:GGG:G	acceptor_gain	1.0000
10:22391728:GGGT:G	acceptor_gain	1.0000
10:22391728:GGGTG:G	acceptor_gain	1.0000

AlphaMissense

3289 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:22411035:T:A	L440Q	0.998
10:22411035:T:C	L440P	0.998
10:22411056:G:C	R447P	0.998
10:22411065:T:C	F450S	0.998
10:22411035:T:G	L440R	0.997
10:22411068:T:A	V451E	0.997
10:22411083:T:C	L456P	0.997
10:22391814:G:A	G364E	0.996
10:22391834:G:C	A371P	0.996
10:22411157:T:G	Y481D	0.996
10:22416626:T:C	S490P	0.996
10:22389269:C:A	A321E	0.995
10:22391835:C:A	A371E	0.995
10:22411092:T:A	V459D	0.995
10:22416620:T:G	Y488D	0.995
10:22389268:G:C	A321P	0.994
10:22391813:G:A	G364R	0.994
10:22391813:G:C	G364R	0.994
10:22411083:T:A	L456H	0.994
10:22411170:T:A	I485K	0.994
10:22416648:T:A	L497H	0.994
10:22416648:T:C	L497P	0.994
10:22389290:C:A	A328E	0.993
10:22391729:G:C	G336R	0.993
10:22391844:T:A	V374D	0.993
10:22401170:G:C	A403P	0.993
10:22411064:T:C	F450L	0.993
10:22411066:T:A	F450L	0.993
10:22411066:T:G	F450L	0.993
10:22411095:A:C	Q460P	0.993

dbSNP variants (sampled 300 via entrez): RS1000013700 (10:22409701 T>C), RS1000034437 (10:22358914 A>G), RS1000061079 (10:22351772 G>A), RS1000096135 (10:22391476 C>A,T), RS1000103729 (10:22374272 G>C), RS1000120370 (10:22399326 C>T), RS1000121359 (10:22377967 T>C), RS1000140889 (10:22387793 T>A,C), RS1000167826 (10:22393912 T>G), RS1000193966 (10:22343949 G>A,C), RS1000393338 (10:22401355 A>T), RS1000492693 (10:22399039 G>A,T), RS1000514221 (10:22364669 A>G), RS1000525370 (10:22413858 A>G), RS1000546840 (10:22364363 C>A)

Disease associations

OMIM: gene MIM:605730 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004093_34	Prostate-specific antigen levels	1.000000e-14
GCST007624_6	Positive urgency	8.000000e-07
GCST008839_320	Height	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006946	behavioural disinhibition measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	9
mercuric bromide	decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	increases abundance, increases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
entinostat	increases 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
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	increases expression	1
Aspirin	increases expression	1
Cadmium	decreases expression, increases abundance	1
Coal	increases abundance, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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