SPAG16

Summary

SPAG16 (sperm associated antigen 16, HGNC:23225) is a protein-coding gene on chromosome 2q34, encoding Sperm-associated antigen 16 protein (Q8N0X2). Necessary for sperm flagellar function.

Cilia and flagella are comprised of a microtubular backbone, the axoneme, which is organized by the basal body and surrounded by plasma membrane. SPAG16 encodes 2 major proteins that associate with the axoneme of sperm tail and the nucleus of postmeiotic germ cells, respectively (Zhang et al., 2007 [PubMed 17699735]).

Source: NCBI Gene 79582 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 117 total
• MANE Select transcript: NM_024532

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23225
Approved symbol	SPAG16
Name	sperm associated antigen 16
Location	2q34
Locus type	gene with protein product
Status	Approved
Aliases	PF20, FLJ22724, DKFZp666P1710, WDR29
Ensembl gene	ENSG00000144451
Ensembl biotype	protein_coding
OMIM	612173
Entrez	79582

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000331683, ENST00000406979, ENST00000413312, ENST00000414961, ENST00000420497, ENST00000432529, ENST00000440779, ENST00000447990, ENST00000451561, ENST00000452556, ENST00000480494

RefSeq mRNA: 2 — MANE Select: NM_024532 NM_001025436, NM_024532

CCDS: CCDS2396, CCDS46508

Canonical transcript exons

ENST00000331683 — 16 exons

Exon	Start	End
ENSE00003463276	213489963	213490090
ENSE00003554476	213296064	213296110
ENSE00003563440	213340163	213340270
ENSE00003586615	213929960	213930145
ENSE00003589891	213297262	213297357
ENSE00003608491	214013951	214014077
ENSE00003611866	214149140	214149266
ENSE00003617511	213375010	213375119
ENSE00003639036	214108196	214108261
ENSE00003639771	213310059	213310177
ENSE00003640649	214410140	214410501
ENSE00003646336	213364076	213364145
ENSE00003656735	213317219	213317356
ENSE00003661188	213350528	213350645
ENSE00003675363	213862485	213862628
ENSE00003843700	213284464	213284619

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4686 / max 285.4464, expressed in 1580 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25057	19.3671	1580
25059	0.1015	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	97.91	gold quality
epithelium of bronchus	UBERON:0002031	97.07	gold quality
bronchus	UBERON:0002185	96.82	gold quality
ventricular zone	UBERON:0003053	96.73	gold quality
corpus callosum	UBERON:0002336	96.29	gold quality
right uterine tube	UBERON:0001302	96.06	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.55	gold quality
spinal cord	UBERON:0002240	95.33	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.30	gold quality
calcaneal tendon	UBERON:0003701	95.19	gold quality
ganglionic eminence	UBERON:0004023	93.56	gold quality
superior vestibular nucleus	UBERON:0007227	93.42	gold quality
nucleus accumbens	UBERON:0001882	93.36	gold quality
amygdala	UBERON:0001876	93.23	gold quality
putamen	UBERON:0001874	92.82	gold quality
right testis	UBERON:0004534	92.82	gold quality
left testis	UBERON:0004533	92.78	gold quality
hypothalamus	UBERON:0001898	92.77	gold quality
endothelial cell	CL:0000115	92.65	gold quality
epithelium of nasopharynx	UBERON:0001951	92.63	gold quality
nasopharynx	UBERON:0001728	92.61	gold quality
testis	UBERON:0000473	92.60	gold quality
subthalamic nucleus	UBERON:0001906	92.51	gold quality
choroid plexus epithelium	UBERON:0003911	92.50	gold quality
caudate nucleus	UBERON:0001873	92.47	gold quality
inferior vagus X ganglion	UBERON:0005363	92.35	gold quality
substantia nigra	UBERON:0002038	92.22	gold quality
midbrain	UBERON:0001891	92.04	gold quality
medulla oblongata	UBERON:0001896	91.95	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.63
E-MTAB-5061	yes	9.15
E-MTAB-9388	yes	8.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting SPAG16, 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-548AT-5P	99.96	70.83	2666
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-4494	97.86	64.93	850
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-4771	97.43	67.69	596
HSA-MIR-4298	97.26	66.59	765

Literature-anchored findings (GeneRIF, showing 8)

• Data describe the cloning of human and mouse Pf20 proteins that interact with Spag6 protein. (PMID:12391165)
• Heterozygous mutation that affects both SPAG16L and SPAG16S does not cause male infertility in man, but is associated with reduced stability of the interacting proteins of the central apparatus. (PMID:17699735)
• Analysis of SPAG16 regions encoding conserved WD repeats revealed no evidence for association of mutations or genetic variation with sperm motility in infertile males. (PMID:22963137)
• SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive rheumatoid arthritis. (PMID:23956247)
• SPAG16 is a novel autoantibody target in a subgroup of MS patients and in combination with other diagnostic criteria, elevated levels of anti-SPAG16 Abs could be used as a biomarker for diagnosis. (PMID:25086173)
• Short-SOX5 regulates transcription of human SPAG16L gene via directly binding to the promoter of SPAG16L. (PMID:28137312)
• Identification and Classification of Novel Genetic Variants: En Route to the Diagnosis of Primary Ciliary Dyskinesia. (PMID:34445527)
• Genetic variant in SPAG16 is associated with the susceptibility of ACPA-positive rheumatoid arthritis possibly via regulation of MMP-3. (PMID:36434627)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spag16	ENSMUSG00000053153
rattus_norvegicus	Spag16	ENSRNOG00000054475
rattus_norvegicus		ENSRNOG00000075101

Protein

Protein identifiers

Sperm-associated antigen 16 protein — Q8N0X2 (reviewed: Q8N0X2)

Alternative names: Pf20 protein homolog

All UniProt accessions (8): Q8N0X2, A0A0C4DG20, E7EWV3, E9PE90, F8WB32, F8WBQ0, F8WBY1, H0Y811

UniProt curated annotations — full annotation on UniProt →

Function. Necessary for sperm flagellar function. Plays a role in motile ciliogenesis. May help to recruit STK36 to the cilium or apical surface of the cell to initiate subsequent steps of construction of the central pair apparatus of motile cilia.

Subunit / interactions. Interacts with SPAG6 and STK36. Interacts with CFAP65.

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

Tissue specificity. Isoform 1 is detected in testis. Isoform 4 is detected in testis and brain, and at lower levels in kidney, heart, pancreas, thyroid, ovary, adrenal gland, spinal cord, trachea and liver.

Post-translational modifications. Phosphorylated by TSSK2.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8N0X2-1	1, PF20 variant 1a	yes
Q8N0X2-2	2
Q8N0X2-3	3
Q8N0X2-4	4, PF20 variant 2a
Q8N0X2-5	5

RefSeq proteins (2): NP_001020607, NP_078808* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR050995	WD-F-box_domain-protein	Family

Pfam: PF00400

UniProt features (28 total): splice variant 10, repeat 7, sequence variant 3, sequence conflict 3, compositionally biased region 2, chain 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N0X2-F1	77.12	0.45

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 118 (showing top): GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_MALE_GAMETE_GENERATION, SMID_BREAST_CANCER_LUMINAL_B_UP, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_MICROTUBULE_BUNDLE_FORMATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MOTILE_CILIUM_ASSEMBLY, RFX1_02, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_AXONEME_ASSEMBLY

GO Biological Process (6): sperm axoneme assembly (GO:0007288), axoneme assembly (GO:0035082), cilium assembly (GO:0060271), cerebrospinal fluid circulation (GO:0090660), mucociliary clearance (GO:0120197), cell projection organization (GO:0030030)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), axoneme (GO:0005930), sperm flagellum (GO:0036126), axonemal central apparatus (GO:1990716), 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
axoneme assembly	2
epithelial cilium movement involved in extracellular fluid movement	2
developmental process involved in reproduction	1
sperm flagellum assembly	1
microtubule bundle formation	1
cellular component assembly	1
cilium assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
nervous system process	1
respiratory system process	1
cellular component organization	1
binding	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
9+2 motile cilium	1
axoneme	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

500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAG16	SPAG6	O75602	990
SPAG16	MEIG1	Q5JSS6	961
SPAG16	SPAG17	Q6Q759	673
SPAG16	HYDIN	Q4G0P3	619
SPAG16	SPAG8	Q99932	570
SPAG16	SPEF1	Q9Y4P9	479
SPAG16	CFAP221	Q4G0U5	475
SPAG16	ODF2	Q5BJF6	435
SPAG16	RSPH3	Q86UC2	433
SPAG16	DNAAF2	Q9NVR5	415
SPAG16	RSPH4A	Q5TD94	370
SPAG16	DPCD	Q9BVM2	370
SPAG16	VWC2	Q2TAL6	364
SPAG16	CCDC146	Q8IYE0	356
SPAG16	A0A0G2JN59	A0A0G2JN59	356

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SPAG16	ADCY6	psi-mi:“MI:0915”(physical association)	0.000
SPAG16	TCHP	psi-mi:“MI:0915”(physical association)	0.000
SPAG16	SETD5	psi-mi:“MI:0915”(physical association)	0.000
SPAG16	rpoH	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): SETD5 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), TCHP (Affinity Capture-MS), SPAG16 (Two-hybrid), MRPL1 (Two-hybrid), AP3M1 (Two-hybrid), VPS39 (Cross-Linking-MS (XL-MS)), SPAG16 (Affinity Capture-Luminescence)

ESM2 similar proteins: A0JP70, A2CEH0, B4GIJ0, D3ZW91, F6ZT52, O54927, Q05B17, Q16MY0, Q28I85, Q28YY2, Q2TBP4, Q32PG3, Q3U821, Q4R2Z6, Q4V7Z1, Q4V837, Q5BIM8, Q5F3K4, Q5RAW8, Q5RD06, Q5RHI5, Q5ZIU8, Q5ZLG9, Q66JG1, Q68EI0, Q6DFC6, Q6GPU3, Q6KAU8, Q6P1V3, Q6P1W0, Q6PFM9, Q6PJI9, Q7T0P4, Q7T2F6, Q7ZVF0, Q8BG40, Q8BH57, Q8BHD1, Q8C0M0, Q8IWA0

Diamond homologs: P93107, Q8K450, Q8N0X2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	11
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

7919 predictions. Top by Δscore:

Variant	Effect	Δscore
2:213284617:A:T	donor_gain	1.0000
2:213296036:T:TA	acceptor_gain	1.0000
2:213297252:T:A	acceptor_gain	1.0000
2:213297254:T:TA	acceptor_gain	1.0000
2:213297337:GC:G	donor_gain	1.0000
2:213297344:A:G	donor_gain	1.0000
2:213297353:TTTTG:T	donor_gain	1.0000
2:213297354:TTTGG:T	donor_loss	1.0000
2:213297355:TTGG:T	donor_loss	1.0000
2:213297356:TGGTG:T	donor_loss	1.0000
2:213297357:GGT:G	donor_loss	1.0000
2:213297358:G:GG	donor_gain	1.0000
2:213297358:GTGAG:G	donor_loss	1.0000
2:213297359:T:TG	donor_loss	1.0000
2:213297360:GA:G	donor_loss	1.0000
2:213317349:GCAGC:G	donor_gain	1.0000
2:213317352:GCTGA:G	donor_gain	1.0000
2:213317353:C:CG	donor_gain	1.0000
2:213317353:C:G	donor_gain	1.0000
2:213317355:GA:G	donor_gain	1.0000
2:213317357:G:GG	donor_gain	1.0000
2:213340161:A:AG	acceptor_gain	1.0000
2:213340162:G:GG	acceptor_gain	1.0000
2:213340162:GC:G	acceptor_gain	1.0000
2:213340162:GCAAA:G	acceptor_gain	1.0000
2:213340269:GG:G	donor_gain	1.0000
2:213340270:GG:G	donor_gain	1.0000
2:213364067:A:AG	acceptor_gain	1.0000
2:213364068:C:G	acceptor_gain	1.0000
2:213364071:TTTA:T	acceptor_loss	1.0000

AlphaMissense

4203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:214410152:C:A	A578D	0.996
2:213930075:T:A	W444R	0.995
2:213930075:T:C	W444R	0.995
2:213930132:T:A	W463R	0.995
2:213930132:T:C	W463R	0.995
2:214410307:T:A	W630R	0.995
2:214410307:T:C	W630R	0.995
2:213930100:C:A	A452D	0.994
2:214149185:T:A	W547R	0.994
2:214149185:T:C	W547R	0.994
2:213929982:A:C	S413R	0.992
2:213929984:T:A	S413R	0.992
2:213929984:T:G	S413R	0.992
2:214014006:T:C	F486L	0.992
2:214014008:T:A	F486L	0.992
2:214014008:T:G	F486L	0.992
2:213862540:T:A	W376R	0.991
2:213862540:T:C	W376R	0.991
2:213929974:C:A	A410D	0.991
2:214014063:T:A	W505R	0.991
2:214014063:T:C	W505R	0.991
2:213340201:G:C	R192P	0.990
2:213930134:G:C	W463C	0.990
2:213930134:G:T	W463C	0.990
2:214149153:C:A	A536E	0.990
2:213930123:A:C	S460R	0.989
2:213930125:C:A	S460R	0.989
2:213930125:C:G	S460R	0.989
2:214149155:T:C	S537P	0.989
2:214410151:G:C	A578P	0.989

dbSNP variants (sampled 300 via entrez): RS1000001353 (2:213315510 C>T), RS1000003027 (2:213839796 G>T), RS1000005185 (2:214299948 G>A), RS1000007459 (2:213990996 A>T), RS1000009181 (2:213591004 G>A), RS1000010763 (2:213784766 C>T), RS1000016243 (2:213525058 A>C,G), RS1000016612 (2:213536600 T>C), RS1000017582 (2:214121569 A>C,G,T), RS1000018296 (2:213315062 C>G), RS1000024115 (2:213740474 C>A,T), RS1000026992 (2:213713794 G>A,T), RS1000027777 (2:213827120 G>A,C), RS1000028203 (2:213911074 A>G,T), RS1000030722 (2:213293577 G>T)

Disease associations

OMIM: gene MIM:612173 | disease phenotypes: MIM:617468, MIM:208150

GenCC curated gene-disease

Mondo (2): arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (2): Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001762_284	Obesity-related traits	8.000000e-06
GCST001762_868	Obesity-related traits	2.000000e-06
GCST002238_3	Contrast sensitivity	1.000000e-06
GCST002248_4	Fasting insulin (dietary factor interaction)	6.000000e-07
GCST002253_3	Homeostasis model assessment of insulin resistance (dietary factor interaction)	1.000000e-06
GCST002783_480	Body mass index	3.000000e-06
GCST003265_224	Post bronchodilator FEV1/FVC ratio in COPD	5.000000e-06
GCST003265_225	Post bronchodilator FEV1/FVC ratio in COPD	4.000000e-06
GCST003265_229	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_231	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_324	Post bronchodilator FEV1/FVC ratio in COPD	8.000000e-07
GCST003265_325	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_384	Post bronchodilator FEV1/FVC ratio in COPD	9.000000e-07
GCST004408_2	HIV-associated neurocognitive disorder (mild neurocognitive disorder)	7.000000e-06
GCST005023_36	Initial pursuit acceleration	8.000000e-08
GCST007205_8	Schizophrenia	5.000000e-06
GCST007543_1	Attention deficit hyperactivity disorder	9.000000e-07
GCST008151_40	Waist circumference	5.000000e-06
GCST008160_85	Waist circumference	5.000000e-06
GCST009600_84	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	7.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0005119	antioxidant measurement
EFO:0005116	urinary metabolite measurement
EFO:0005419	contrast sensitivity measurement
EFO:0008111	diet measurement
EFO:0004501	HOMA-IR
EFO:0004340	body mass index
EFO:0004713	FEV/FVC ratio
EFO:0007948	HIV-associated neurocognitive disorder
EFO:0007982	mild neurocognitive disorder
EFO:0008434	initial pursuit acceleration

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs35945601	SPAG16		0.00	0

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Estradiol	affects expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	increases reaction, affects binding	1
eprenetapopt	affects expression, affects reaction	1
Acetaminophen	decreases expression	1
Cisplatin	decreases expression	1
Cytarabine	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methapyrilene	increases methylation	1
Phenobarbital	affects expression	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin M1	decreases expression	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Genistein	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3