SPHKAP

Summary

SPHKAP (SPHK1 interactor, AKAP domain containing, HGNC:30619) is a protein-coding gene on chromosome 2q36.3, encoding A-kinase anchor protein SPHKAP (Q2M3C7). Anchoring protein that binds preferentially to the type I regulatory subunit of c-AMP-dependent protein kinase (PKA type I) and targets it to distinct subcellular compartments.

Enables protein kinase A binding activity. Predicted to be located in Z disc. Predicted to be active in mitochondrion.

Source: NCBI Gene 80309 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 268 total
• MANE Select transcript: NM_001142644

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30619
Approved symbol	SPHKAP
Name	SPHK1 interactor, AKAP domain containing
Location	2q36.3
Locus type	gene with protein product
Status	Approved
Aliases	SKIP
Ensembl gene	ENSG00000153820
Ensembl biotype	protein_coding
OMIM	611646
Entrez	80309

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000344657, ENST00000392056, ENST00000490603

RefSeq mRNA: 2 — MANE Select: NM_001142644 NM_001142644, NM_030623

CCDS: CCDS33389, CCDS46537

Canonical transcript exons

ENST00000392056 — 12 exons

Exon	Start	End
ENSE00001012562	227995509	227995694
ENSE00001123961	228016406	228020156
ENSE00001133962	228021711	228021966
ENSE00001133971	228025394	228025528
ENSE00001183812	228108832	228108939
ENSE00001318026	228027484	228027543
ENSE00001327717	228131980	228132085
ENSE00001376193	227991000	227991184
ENSE00001510556	228181567	228181687
ENSE00001842714	227979955	227981860
ENSE00003639125	227993534	227993620
ENSE00003649658	227991274	227991326

Expression profiles

Bgee: expression breadth ubiquitous, 127 present calls, max score 99.61.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9404 / max 343.3250, expressed in 153 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34366	0.7696	125
34367	0.3302	96
34364	0.2427	64
34368	0.1642	56
34369	0.1268	37
34373	0.1103	34
34365	0.1039	43
34371	0.0322	9
34372	0.0314	9
34370	0.0291	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.61	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.22	gold quality
myocardium	UBERON:0002349	97.38	gold quality
heart right ventricle	UBERON:0002080	97.11	gold quality
cerebellar vermis	UBERON:0004720	92.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.56	gold quality
cerebellum	UBERON:0002037	90.96	gold quality
cerebellar cortex	UBERON:0002129	90.68	gold quality
cerebellar hemisphere	UBERON:0002245	90.59	gold quality
entorhinal cortex	UBERON:0002728	90.09	gold quality
cortical plate	UBERON:0005343	89.60	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.07	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.89	gold quality
cardiac ventricle	UBERON:0002082	86.17	gold quality
heart left ventricle	UBERON:0002084	85.91	gold quality
Ammon’s horn	UBERON:0001954	85.47	gold quality
middle temporal gyrus	UBERON:0002771	84.15	gold quality
superior frontal gyrus	UBERON:0002661	83.63	gold quality
postcentral gyrus	UBERON:0002581	81.43	gold quality
endothelial cell	CL:0000115	81.34	silver quality
apex of heart	UBERON:0002098	80.97	gold quality
cardiac atrium	UBERON:0002081	80.47	gold quality
heart	UBERON:0000948	80.18	gold quality
parietal lobe	UBERON:0001872	79.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.49	silver quality
dorsal root ganglion	UBERON:0000044	79.47	gold quality
right atrium auricular region	UBERON:0006631	79.26	gold quality
prefrontal cortex	UBERON:0000451	78.94	gold quality
cerebral cortex	UBERON:0000956	78.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

119 targeting SPHKAP, 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-3134	100.00	66.43	777
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 10)

• cloning and characterization; results indicate that SKIP is a novel protein likely to play a regulatory role in the modulation of sphingosine kinase type 1 (SPHK1) activity (PMID:12080051)
• experiments demonstrate that sphingosine kinase 1/sphingosine-1-phosphate are important components of the transforming growth factor-beta signaling pathway involved in up-regulation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) (PMID:15485866)
• Uterine expression of SphK1 mediates processes involved in growth and differentiation of uterine tissues during pregnancy. (PMID:17164439)
• Hyperglycemia stimulates SK1 activity via protein kinase C and oxidative stress-dependent pathways, leading to decreased apoptosis in vvascular smooth muscle. (PMID:17325258)
• HIF-1 and HIF-2 have roles in SK1 upregulation during hypoxia in glioma cells (PMID:18055454)
• sphingosine kinase type 1-interacting protein can be considered as the first mammalian A-kinase-anchoring proteins that preferentially binds to regulatory subunit 1 of cAMP-dependent protein kinase. (PMID:20394097)
• SKIP is an entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria. (PMID:22084075)
• Results showed that DPP6, SPHKAP and ID4 were down regulated in acute myeloid leukemia (AML) patients. (PMID:22479372)
• Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function. (PMID:32161116)
• SphK1 Promotes Cancer Progression through Activating JAK/STAT Pathway and Up-Regulating S1PR1 Expression in Colon Cancer Cells. (PMID:33797381)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sphkap	ENSDARG00000017429
mus_musculus	Sphkap	ENSMUSG00000026163
rattus_norvegicus	Sphkap	ENSRNOG00000016388

Paralogs (3): AKAP11 (ENSG00000023516), AKAP3 (ENSG00000111254), AKAP4 (ENSG00000147081)

Protein

Protein identifiers

A-kinase anchor protein SPHKAP — Q2M3C7 (reviewed: Q2M3C7)

Alternative names: SPHK1-interactor and AKAP domain-containing protein, Sphingosine kinase type 1-interacting protein

All UniProt accessions (1): Q2M3C7

UniProt curated annotations — full annotation on UniProt →

Function. Anchoring protein that binds preferentially to the type I regulatory subunit of c-AMP-dependent protein kinase (PKA type I) and targets it to distinct subcellular compartments. May act as a converging factor linking cAMP and sphingosine signaling pathways. Plays a regulatory role in the modulation of SPHK1.

Subunit / interactions. Interacts (via the PKA-RII subunit binding domain) with the RI subunit of PKA. Interacts with SPHK1; the interaction greatly reduces SPHK1 activity.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in heart. Both isoforms abundantly expressed in ventricle. Also expressed in spleen, ovary and brain.

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.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2M3C7-1	1	yes
Q2M3C7-2	2

RefSeq proteins (2): NP_001136116, NP_085126 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008382	SPHK1-interactor_AKAP_110	Family
IPR018292	AKAP_110_C	Domain

Pfam: PF05716

UniProt features (34 total): region of interest 8, modified residue 8, compositionally biased region 6, sequence variant 5, sequence conflict 5, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2M3C7-F1	47.68	0.04

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 (8): 1025, 1085, 1107, 1120, 1121, 1124, 1259, 1288

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 72 (showing top): BIOCARTA_EDG1_PATHWAY, GOMF_PROTEIN_KINASE_A_BINDING, MIKKELSEN_ES_ICP_WITH_H3K4ME3, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_D, MIR548N, MIR23A_3P_MIR23B_3P, MIR23C, MIR3121_3P, MIR3529_3P, MIR4533, MIR5196_5P, MIR4747_5P, MIR4801, MIR4528, MIR4427

GO Biological Process (0):

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

GO Cellular Component (2): cytoplasm (GO:0005737), mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1272 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPHKAP	SPHK1	Q9NYA1	876
SPHKAP	AKAP10	O43572	594
SPHKAP	AKAP1	Q92667	536
SPHKAP	AKAP19	P0C876	514
SPHKAP	PID1	Q7Z2X4	473
SPHKAP	ENPP5	Q9UJA9	457
SPHKAP	PLBD1	Q6P4A8	437
SPHKAP	SCGB3A2	Q96PL1	431
SPHKAP	PPP3CB	P16298	428
SPHKAP	PTBP2	Q9UKA9	426
SPHKAP	C4BPB	P20851	422
SPHKAP	PCDHAC2	Q9Y5I4	401
SPHKAP	AKAP7	O43687	397
SPHKAP	DEPDC5	O75140	397
SPHKAP	VRK1	Q99986	395

IntAct

11 interactions, top by confidence:

A	B	Type	Score
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
SPHK1	SPHKAP	psi-mi:“MI:0915”(physical association)	0.600
SPHKAP	SPHK1	psi-mi:“MI:0403”(colocalization)	0.600
	SPHKAP	psi-mi:“MI:0915”(physical association)	0.560
PPTC7	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
	SPHKAP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): SPHKAP (Affinity Capture-MS), SPHKAP (Affinity Capture-MS), SPHKAP (Affinity Capture-MS), SYCE1L (Two-hybrid), SPHKAP (Affinity Capture-MS), RPL29 (Cross-Linking-MS (XL-MS)), HSP90AA1 (Cross-Linking-MS (XL-MS)), HSP90AB1 (Cross-Linking-MS (XL-MS)), SPHKAP (Cross-Linking-MS (XL-MS)), SPHKAP (Cross-Linking-MS (XL-MS)), SPHKAP (Two-hybrid)

ESM2 similar proteins: A0A140LI88, A4D1E1, D3Z987, D3ZUC6, E5FYH0, E5FYH1, E9Q3S4, F6ULY3, F7DF15, G3S077, G7H7V7, G7NY55, O35923, O54952, O88491, O95405, P38398, P48754, P51587, P97929, Q0VBV7, Q0VGT4, Q2M3C7, Q3V089, Q56UN5, Q5DTT3, Q5F2C3, Q5VWN6, Q61493, Q68DQ2, Q6J6I8, Q6J6I9, Q6J6J0, Q6NSW3, Q6ZP01, Q7TSY8, Q7Z570, Q80U44, Q864S8, Q864U1

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	241
Likely benign	23
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2849 predictions. Top by Δscore:

Variant	Effect	Δscore
2:227995523:A:AC	donor_gain	1.0000
2:227995524:C:CC	donor_gain	1.0000
2:227995524:CTGAG:C	donor_gain	1.0000
2:227995528:G:C	donor_gain	1.0000
2:227995563:T:TA	donor_gain	1.0000
2:227995693:CA:C	acceptor_gain	1.0000
2:227995695:C:CC	acceptor_gain	1.0000
2:228021710:CCGTT:C	donor_gain	1.0000
2:228021714:T:A	donor_gain	1.0000
2:228021737:T:A	donor_gain	1.0000
2:228021773:T:TA	donor_gain	1.0000
2:228021962:GGGCA:G	acceptor_gain	1.0000
2:228021963:GGCA:G	acceptor_gain	1.0000
2:228021963:GGCAC:G	acceptor_gain	1.0000
2:228021964:GCA:G	acceptor_gain	1.0000
2:228021964:GCAC:G	acceptor_gain	1.0000
2:228021965:CA:C	acceptor_gain	1.0000
2:228021965:CAC:C	acceptor_gain	1.0000
2:228021965:CACTA:C	acceptor_gain	1.0000
2:228021966:AC:A	acceptor_gain	1.0000
2:228021967:C:CC	acceptor_gain	1.0000
2:228021967:CTAA:C	acceptor_gain	1.0000
2:228021973:G:C	acceptor_gain	1.0000
2:228021973:G:GC	acceptor_gain	1.0000
2:228025388:TCTTA:T	donor_loss	1.0000
2:228025389:CTTAC:C	donor_loss	1.0000
2:228025390:TTA:T	donor_loss	1.0000
2:228025391:TA:T	donor_loss	1.0000
2:228025392:A:AC	donor_gain	1.0000
2:228025392:A:T	donor_loss	1.0000

AlphaMissense

11272 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:227991071:A:G	W1630R	0.999
2:227991071:A:T	W1630R	0.999
2:228017467:A:C	F1129L	0.998
2:228017467:A:T	F1129L	0.998
2:228017468:A:G	F1129S	0.998
2:228017469:A:G	F1129L	0.998
2:228017804:A:G	L1017P	0.998
2:228017846:A:C	I1003S	0.998
2:228017846:A:G	I1003T	0.998
2:228018033:C:G	A941P	0.998
2:228017982:A:G	W958R	0.997
2:228017982:A:T	W958R	0.997
2:228018018:C:G	A946P	0.997
2:228018021:C:G	A945P	0.997
2:227991064:G:T	A1632D	0.996
2:227991076:A:G	L1628P	0.996
2:228017846:A:T	I1003N	0.996
2:228108900:A:G	W60R	0.996
2:228108900:A:T	W60R	0.996
2:228017272:G:C	F1194L	0.995
2:228017272:G:T	F1194L	0.995
2:228017274:A:G	F1194L	0.995
2:228017491:G:C	S1121R	0.995
2:228017491:G:T	S1121R	0.995
2:228017493:T:G	S1121R	0.995
2:228017816:A:G	L1013P	0.995
2:228017977:A:C	F959L	0.995
2:228017977:A:T	F959L	0.995
2:228017979:A:G	F959L	0.995
2:227981733:A:G	L1696P	0.994

dbSNP variants (sampled 300 via entrez): RS1000004721 (2:228143142 C>A,T), RS1000016021 (2:227980752 G>A), RS1000022879 (2:228172273 G>C,T), RS1000025206 (2:228178731 A>G), RS1000033602 (2:227999066 A>T), RS1000035795 (2:228093935 AGGATGGTAT>A), RS1000071075 (2:228096059 A>G), RS1000085684 (2:227998791 G>A), RS1000096044 (2:228041455 G>A), RS1000108193 (2:228164713 C>G), RS1000125409 (2:228047921 T>A), RS1000133772 (2:228138244 A>G), RS1000146150 (2:228086759 G>A), RS1000163950 (2:228153162 G>A,T), RS1000173846 (2:228075794 C>G)

Disease associations

OMIM: gene MIM:611646 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001959_4	Eating disorders (purging via substances)	2.000000e-06
GCST002591_18	Lewy body disease	6.000000e-06
GCST002591_26	Lewy body disease	8.000000e-06
GCST003672_9	Docetaxel-induced peripheral neuropathy in metastatic castrate-resistant prostate cancer	5.000000e-06
GCST006409_13	Allergic rhinitis	2.000000e-10
GCST006463_7	Urinary albumin excretion (no hypertensive medication)	1.000000e-10
GCST006586_8	Urinary albumin excretion	9.000000e-23
GCST006867_18	Type 2 diabetes	3.000000e-08
GCST007205_1	Schizophrenia	4.000000e-10
GCST008595_73	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	4.000000e-08
GCST009640_16	Urinary albumin-to-creatinine ratio	9.000000e-21
GCST009798_81	Asthma	1.000000e-09
GCST010988_128	Adult body size	2.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006799	Lewy body dementia measurement
EFO:0004285	albuminuria
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0007778	urinary albumin to creatinine ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
Doxorubicin	decreases expression	2
terbufos	increases methylation	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
bisphenol S	decreases methylation	1
Decitabine	increases expression	1
Sunitinib	decreases expression	1
Cadmium	decreases expression	1
Caffeine	increases phosphorylation	1
Diethylhexyl Phthalate	decreases expression	1
Fonofos	increases methylation	1
Methapyrilene	increases methylation	1
Parathion	increases methylation	1
Triclosan	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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