AKAP3

Summary

AKAP3 (A-kinase anchoring protein 3, HGNC:373) is a protein-coding gene on chromosome 12p13.32, encoding A-kinase anchor protein 3 (O75969). Structural component of sperm fibrous sheath.

This gene encodes a member of A-kinase anchoring proteins (AKAPs), a family of functionally related proteins that target protein kinase A to discrete locations within the cell. The encoded protein is reported to participate in protein-protein interactions with the R-subunit of the protein kinase A as well as sperm-associated proteins. This protein is expressed in spermatozoa and localized to the acrosomal region of the sperm head as well as the length of the principal piece. It may function as a regulator of motility, capacitation, and the acrosome reaction.

Source: NCBI Gene 10566 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 82 (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 149 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_001278309

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:373
Approved symbol	AKAP3
Name	A-kinase anchoring protein 3
Location	12p13.32
Locus type	gene with protein product
Status	Approved
Aliases	FSP95, SOB1, AKAP110, CT82
Ensembl gene	ENSG00000111254
Ensembl biotype	protein_coding
OMIM	604689
Entrez	10566

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000228850, ENST00000536414, ENST00000540967, ENST00000541484, ENST00000544636, ENST00000545990, ENST00000861465, ENST00000861466, ENST00000861467, ENST00000861468, ENST00000861469, ENST00000934728, ENST00000934729, ENST00000934730, ENST00000941577, ENST00000941578

RefSeq mRNA: 2 — MANE Select: NM_001278309 NM_001278309, NM_006422

CCDS: CCDS8531

Canonical transcript exons

ENST00000228850 — 6 exons

Exon	Start	End
ENSE00000997511	4641899	4642004
ENSE00000997513	4615518	4615894
ENSE00002304935	4645055	4645192
ENSE00003842118	4648745	4649051
ENSE00003842372	4638101	4638196
ENSE00003895268	4626496	4628805

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 95.43.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9061 / max 184.8956, expressed in 354 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129028	0.6971	351
129025	0.1245	3
129027	0.0464	4
129026	0.0293	3
129024	0.0089	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	95.43	gold quality
right testis	UBERON:0004534	95.16	gold quality
testis	UBERON:0000473	92.88	gold quality
sperm	CL:0000019	92.01	gold quality
male germ cell	CL:0000015	91.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.91	gold quality
adult organism	UBERON:0007023	83.57	gold quality
left ventricle myocardium	UBERON:0006566	76.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.23	gold quality
islet of Langerhans	UBERON:0000006	74.94	gold quality
cardiac atrium	UBERON:0002081	72.11	gold quality
right atrium auricular region	UBERON:0006631	71.72	gold quality
right uterine tube	UBERON:0001302	68.99	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	68.85	gold quality
pancreas	UBERON:0001264	68.69	gold quality
body of pancreas	UBERON:0001150	67.13	gold quality
spinal cord	UBERON:0002240	65.98	gold quality
ventricular zone	UBERON:0003053	64.80	gold quality
rectum	UBERON:0001052	64.78	gold quality
heart	UBERON:0000948	64.07	gold quality
right adrenal gland	UBERON:0001233	64.06	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	63.83	gold quality
prefrontal cortex	UBERON:0000451	63.78	gold quality
inferior olivary complex	UBERON:0002127	63.39	gold quality
heart left ventricle	UBERON:0002084	62.99	gold quality
mucosa of transverse colon	UBERON:0004991	62.90	gold quality
left adrenal gland	UBERON:0001234	62.65	gold quality
smooth muscle tissue	UBERON:0001135	62.36	gold quality
hindlimb stylopod muscle	UBERON:0004252	62.32	gold quality
cardiac ventricle	UBERON:0002082	62.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.87
E-CURD-10	no	1.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting AKAP3, 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-4668-3P	100.00	68.74	2635
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-5011-3P	98.63	64.81	638
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-5088-5P	97.97	64.28	487
HSA-MIR-4446-3P	97.91	64.29	991
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-1233-3P	96.81	65.44	573
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895
HSA-MIR-2909	96.36	67.30	562
HSA-MIR-4693-3P	95.23	65.92	735
HSA-MIR-10396B-5P	94.99	63.57	358
HSA-MIR-1908-5P	94.99	63.41	352
HSA-MIR-663A	94.99	63.54	378
HSA-MIR-3679-5P	94.75	66.46	862
HSA-MIR-1185-5P	94.47	65.95	725
HSA-MIR-1296-5P	93.94	67.71	305

Literature-anchored findings (GeneRIF, showing 12)

• evidence of tyrosine phosphorylation during sperm capacitation (PMID:12509440)
• In Cox multivariate analysis, AKAP3 mRNA expression was found to be a significant predictor of both overall and progression-free survival in patients with poorly differentiated tumors. (PMID:14618620)
• AKAP-3 demonstrates tumor-restricted expression and appears to be associated with worse overall survival. (PMID:16005946)
• AKAP3 is a novel target for protein S-nitrosylation in spermatozoa. (PMID:17683036)
• CABYR variants form a complex not only with the scaffolding protein AKAP3 but also with another RII-like domain-containing protein in the sperm fibrous sheath. (PMID:21240291)
• study reports the isolation of AKAP3 and CTp11 Cancer/testis antigens from hepatocellular carcinoma patient sera (PMID:22941507)
• AKAP3 correlates with triple negative status and disease free survival in breast cancer. (PMID:26458542)
• The present study revealed that one of the major rHuOVGP1-enhanced pY proteins could be AKAP3 of the FS and that rHuOVGP1 is capable of binding to human ZP and its presence in the medium results in an increase in sperm-zona binding. Supplement of rHuOVGP1 in in vitro fertilization media could be beneficial for enhancement of the fertilizing ability of human sperm. (PMID:31254143)
• Protein Kinase A (PRKA) Activity Is Regulated by the Proteasome at the Onset of Human Sperm Capacitation. (PMID:34944009)
• Homozygous variants in AKAP3 induce asthenoteratozoospermia and male infertility. (PMID:35228300)
• Structural modeling of human AKAP3 protein and in silico analysis of single nucleotide polymorphisms associated with sperm motility. (PMID:35256641)
• The cancer-testis antigen a-kinase anchor protein 3 facilitates breast cancer progression via activation of the PTEN/PI3K/AKT/mTOR signaling. (PMID:35322748)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Akap3	ENSMUSG00000030344
rattus_norvegicus	Akap3	ENSRNOG00000059227

Paralogs (3): AKAP11 (ENSG00000023516), AKAP4 (ENSG00000147081), SPHKAP (ENSG00000153820)

Protein

Protein identifiers

A-kinase anchor protein 3 — O75969 (reviewed: O75969)

Alternative names: A-kinase anchor protein 110 kDa, Cancer/testis antigen 82, Fibrous sheath protein of 95 kDa, Fibrousheathin I, Fibrousheathin-1, Protein kinase A-anchoring protein 3, Sperm oocyte-binding protein

All UniProt accessions (4): O75969, F5H2S4, F5H7P4, V9HWD4

UniProt curated annotations — full annotation on UniProt →

Function. Structural component of sperm fibrous sheath. Required for the formation of the subcellular structure of the sperm flagellum, sperm motility and male fertility.

Subunit / interactions. Interacts with ROPN1 and ROPN1L. Interacts with QRICH2.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Cell projection. Cilium. Flagellum.

Tissue specificity. Testis specific; only expressed in spermatids.

Post-translational modifications. Phosphorylated by STK33 during sperm flagella assembly. Phosphorylated on tyrosine residues.

Disease relevance. Spermatogenic failure 82 (SPGF82) [MIM:620353] An autosomal recessive male infertility disorder characterized by asthenoteratozoospermia and multiple morphologic abnormalities of the sperm flagella. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. RII-binding site, predicted to form an amphipathic helix, could participate in protein-protein interactions with a complementary surface on the R-subunit dimer.

Similarity. Belongs to the AKAP110 family.

RefSeq proteins (2): NP_001265238, NP_006413 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008382	SPHK1-interactor_AKAP_110	Family
IPR018292	AKAP_110_C	Domain
IPR020799	AKAP_110	Family

Pfam: PF05716

UniProt features (27 total): sequence variant 10, sequence conflict 6, modified residue 6, region of interest 2, chain 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75969-F1	50.79	0.05

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 (6): 205, 208, 403, 404, 635, 636

Mutagenesis-validated functional residues (1):

Position	Phenotype
131	abolishes interaction with ropn1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 136 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOCC_SECRETORY_GRANULE, KORKOLA_CHORIOCARCINOMA_DN, GCAAGGA_MIR502, RACCACAR_AML_Q6, MORF_RAD51L3, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, MODULE_379, MORF_CTSB, KORKOLA_EMBRYONAL_CARCINOMA_DN, GOBP_CILIUM_MOVEMENT, MORF_IL4, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_BLASTOCYST_DEVELOPMENT

GO Biological Process (7): blastocyst hatching (GO:0001835), cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178), single fertilization (GO:0007338), acrosome reaction (GO:0007340), intracellular protein localization (GO:0008104), flagellated sperm motility (GO:0030317), establishment of protein localization (GO:0045184)

GO Molecular Function (2): protein kinase A binding (GO:0051018), protein binding (GO:0005515)

GO Cellular Component (10): acrosomal vesicle (GO:0001669), nucleus (GO:0005634), cytoplasm (GO:0005737), sperm fibrous sheath (GO:0035686), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), cilium (GO:0005929), cytoplasmic vesicle (GO:0031410), 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
sperm flagellum	3
blastocyst development	1
hatching	1
enzyme-linked receptor protein signaling pathway	1
fertilization	1
membrane fusion involved in acrosome reaction	1
single fertilization	1
reproductive process	1
acrosomal vesicle exocytosis	1
macromolecule localization	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
establishment of localization	1
protein binding	1
binding	1
secretory granule	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoplasm	1
intracellular vesicle	1
cilium	1

Protein interactions and networks

STRING

982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKAP3	ROPN1	Q9HAT0	985
AKAP3	CABYR	O75952	962
AKAP3	SPA17	Q15506	936
AKAP3	ROPN1L	Q96C74	924
AKAP3	RHPN1	Q8TCX5	825
AKAP3	AKAP1	Q92667	801
AKAP3	PRKACA	P17612	624
AKAP3	PRKACG	P22612	620
AKAP3	PRKACB	P22694	613
AKAP3	NDUFAF3	Q9BU61	611
AKAP3	PDE4A	P27815	582
AKAP3	ODF1	Q14990	574
AKAP3	TSGA10	Q9BZW7	535
AKAP3	FSIP2	Q5CZC0	532
AKAP3	GAPDHS	O14556	526

IntAct

10 interactions, top by confidence:

A	B	Type	Score
PRKAR1A	AKAP3	psi-mi:“MI:0914”(association)	0.530
BRAP	AKAP3	psi-mi:“MI:0915”(physical association)	0.510
ROPN1B	AKAP3	psi-mi:“MI:0915”(physical association)	0.510
AKAP3	PRKAR2A	psi-mi:“MI:0915”(physical association)	0.510
AKAP3	ROPN1B	psi-mi:“MI:0915”(physical association)	0.510
PRKAR2A	AKAP3	psi-mi:“MI:0915”(physical association)	0.510
AKAP3	ROPN1L	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (21): AKAP3 (Affinity Capture-MS), AKAP3 (Two-hybrid), AKAP3 (Reconstituted Complex), AKAP3 (Affinity Capture-MS), SPA17 (Reconstituted Complex), AKAP3 (Two-hybrid), AKAP4 (Reconstituted Complex), AKAP3 (Two-hybrid), AKAP3 (Proximity Label-MS), PRKAR2A (Far Western), AKAP3 (Reconstituted Complex), AKAP3 (Affinity Capture-Western), PRKAR2A (Two-hybrid), ROPN1L (Two-hybrid), ROPN1 (Two-hybrid)

ESM2 similar proteins: A0A0R4I9Y1, A0A0R4IBK5, A2AN08, A2ARZ3, A5WUT8, A6NKT7, B1WBT0, B8RJM0, C9JQI7, E9Q3L2, E9Q555, H2QII6, O08662, O14715, O15050, O43310, O75592, O75969, P0DJD0, P0DJD1, P13864, P42356, P49792, Q0V9S3, Q0VF22, Q24K09, Q2TL32, Q4R6W9, Q4V847, Q63HN8, Q6PB60, Q6PEE2, Q71HP2, Q7TPH6, Q7TPV2, Q7Z3J3, Q80930, Q80TA9, Q810N5, Q811D2

Diamond homologs: O35774, O75969, O77797, O88987, P0C6C0, Q1LV19, Q2M3C7, Q5JQC9, Q60662, Q6NSW3, Q9UKA4, Q62924

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
STK33	“up-regulates quantity by stabilization”	AKAP3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	114
Likely benign	12
Benign	3

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1527677	GRCh37/hg19 12p13.33-13.32(chr12:2790077-5325700)	Pathogenic
2500165	NM_001278309.2(AKAP3):c.2286_2287del (p.His762fs)	Pathogenic
268075	GRCh37/hg19 12p13.33-q24.33(chr12:1-133851895)x3	Pathogenic
58983	GRCh38/hg38 12p13.33-13.32(chr12:2492728-4829842)x1	Pathogenic
625809	GRCh37/hg19 12p13.33-12.3(chr12:189216-15001420)	Pathogenic
2500166	NM_001278309.2(AKAP3):c.44G>A (p.Cys15Tyr)	Likely pathogenic
3063259	GRCh37/hg19 12p13.33-13.31(chr12:2246103-5406692)x1	Likely pathogenic
442073	GRCh37/hg19 12p13.33-13.32(chr12:3256714-4980727)x1	Likely pathogenic

SpliceAI

1705 predictions. Top by Δscore:

Variant	Effect	Δscore
12:4613510:A:AG	acceptor_gain	1.0000
12:4613511:G:GG	acceptor_gain	1.0000
12:4613511:GC:G	acceptor_gain	1.0000
12:4613511:GCA:G	acceptor_gain	1.0000
12:4615890:AGTAG:A	acceptor_gain	1.0000
12:4615891:GTAG:G	acceptor_gain	1.0000
12:4615892:TAG:T	acceptor_gain	1.0000
12:4615895:C:A	acceptor_loss	1.0000
12:4615895:C:CC	acceptor_gain	1.0000
12:4615897:G:C	acceptor_gain	1.0000
12:4631319:A:AG	acceptor_gain	1.0000
12:4631320:A:G	acceptor_gain	1.0000
12:4638095:CCTTA:C	donor_loss	1.0000
12:4638096:CTTAC:C	donor_loss	1.0000
12:4638097:TTA:T	donor_loss	1.0000
12:4638098:TA:T	donor_loss	1.0000
12:4638099:A:AG	donor_loss	1.0000
12:4638204:C:CT	acceptor_gain	1.0000
12:4638205:A:T	acceptor_gain	1.0000
12:4641897:A:AC	donor_gain	1.0000
12:4641898:C:CC	donor_gain	1.0000
12:4641898:CT:C	donor_gain	1.0000
12:4613506:CTTTA:C	acceptor_loss	0.9900
12:4613507:TTTA:T	acceptor_loss	0.9900
12:4613508:TTA:T	acceptor_loss	0.9900
12:4613509:TA:T	acceptor_loss	0.9900
12:4613510:AGCA:A	acceptor_loss	0.9900
12:4613511:G:A	acceptor_loss	0.9900
12:4613511:GCAGA:G	acceptor_gain	0.9900
12:4615891:GTAGC:G	acceptor_gain	0.9900

AlphaMissense

5639 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:4626567:A:G	W779R	0.995
12:4626567:A:T	W779R	0.995
12:4626565:C:A	W779C	0.989
12:4626565:C:G	W779C	0.989
12:4627904:A:G	L333P	0.988
12:4626557:G:T	A782D	0.986
12:4628036:G:T	A289D	0.986
12:4626572:A:G	L777P	0.985
12:4615755:A:G	L849P	0.984
12:4626558:C:G	A782P	0.984
12:4627880:A:G	L341P	0.984
12:4626526:A:C	F792L	0.983
12:4626526:A:T	F792L	0.983
12:4626528:A:G	F792L	0.983
12:4626575:A:T	V776D	0.983
12:4638178:A:G	W7R	0.983
12:4638178:A:T	W7R	0.983
12:4626560:G:T	A781D	0.981
12:4626561:C:G	A781P	0.981
12:4627949:A:G	L318P	0.981
12:4627840:A:C	F354L	0.980
12:4627840:A:T	F354L	0.980
12:4627842:A:G	F354L	0.980
12:4615809:C:G	R831P	0.979
12:4626555:A:G	S783P	0.979
12:4627991:A:G	L304P	0.978
12:4627937:A:G	L322P	0.977
12:4628037:C:G	A289P	0.977
12:4628501:A:G	L134P	0.977
12:4628510:A:G	L131P	0.976

dbSNP variants (sampled 300 via entrez): RS1000084680 (12:4646349 G>A), RS1000283849 (12:4633187 T>C), RS1000284290 (12:4621414 A>C,G), RS1000319855 (12:4636373 C>T), RS1000605328 (12:4637363 C>A), RS1000624168 (12:4644470 C>A), RS1000738308 (12:4644197 G>A), RS1000804866 (12:4640620 A>C), RS1000889523 (12:4623091 T>C), RS1000935465 (12:4626081 G>C), RS1001027437 (12:4615926 G>A), RS1001140052 (12:4631884 G>C), RS1001158739 (12:4615204 A>T), RS1001181998 (12:4643265 A>G), RS1001209635 (12:4615473 C>T)

Disease associations

OMIM: gene MIM:604689 | disease phenotypes: MIM:160120, MIM:620353

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 82	Limited	Unknown

Mondo (2): episodic ataxia type 1 (MONDO:0008047), spermatogenic failure 82 (MONDO:0957249)

Orphanet (2): Episodic ataxia type 1 (Orphanet:37612), Hereditary continuous muscle fiber activity (Orphanet:972)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset
HP:0032558	Absent sperm flagella
HP:0032559	Short sperm flagella
HP:0032560	Coiled sperm flagella
HP:0034011	Reduced progressive sperm motility

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003875_10	Gut microbiota (bacterial taxa)	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ferrous chloride	decreases expression	1
Arsenic Trioxide	increases expression	1
Benzo(a)pyrene	increases methylation	1
Rotenone	decreases expression	1
T-2 Toxin	increases expression	1
Tobacco Smoke Pollution	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford