SPNS2

Summary

SPNS2 (SPNS lysolipid transporter 2, sphingosine-1-phosphate, HGNC:26992) is a protein-coding gene on chromosome 17p13.2, encoding Sphingosine-1-phosphate transporter SPNS2 (Q8IVW8). Lipid transporter that specifically mediates export of sphingosine-1-phosphate (sphing-4-enine 1-phosphate, S1P) and sphinganine-1-phosphate in the lymph, thereby playing a role in lymphocyte trafficking.

The protein encoded by this gene is a transporter of sphingosine 1-phosphate, a secreted lipid that is important in cardiovascular, immunological, and neural development. Defects in this gene are a cause of early onset progressive hearing loss.

Source: NCBI Gene 124976 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive 115 (Moderate, GenCC)
• Clinical variants (ClinVar): 183 total — 2 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_001124758

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26992
Approved symbol	SPNS2
Name	SPNS lysolipid transporter 2, sphingosine-1-phosphate
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	SLC63A2
Ensembl gene	ENSG00000183018
Ensembl biotype	protein_coding
OMIM	612584
Entrez	124976

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 retained_intron, 5 protein_coding

ENST00000329078, ENST00000570641, ENST00000570979, ENST00000571386, ENST00000571668, ENST00000573106, ENST00000573990, ENST00000576635, ENST00000932033, ENST00000947402, ENST00000947403

RefSeq mRNA: 1 — MANE Select: NM_001124758 NM_001124758

CCDS: CCDS42237

Canonical transcript exons

ENST00000329078 — 13 exons

Exon	Start	End
ENSE00001292645	4532542	4532684
ENSE00001296819	4498881	4499417
ENSE00001298756	4525057	4525193
ENSE00001300490	4530632	4530783
ENSE00001312324	4532977	4533129
ENSE00001314429	4513247	4513312
ENSE00001339657	4537453	4539035
ENSE00001741189	4531053	4531119
ENSE00003487327	4533788	4533853
ENSE00003594688	4536263	4536426
ENSE00003603309	4536076	4536174
ENSE00003648510	4536900	4536946
ENSE00003665940	4533243	4533432

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 98.98.

FANTOM5 (CAGE): breadth broad, TPM avg 9.2403 / max 322.0750, expressed in 794 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158897	7.8203	762
158896	0.8920	414
158898	0.4182	245
158899	0.0598	45
158900	0.0500	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.98	gold quality
metanephros cortex	UBERON:0010533	98.04	gold quality
pharyngeal mucosa	UBERON:0000355	97.17	gold quality
kidney epithelium	UBERON:0004819	96.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.91	gold quality
spinal cord	UBERON:0002240	95.36	gold quality
upper arm skin	UBERON:0004263	95.20	silver quality
buccal mucosa cell	CL:0002336	95.10	gold quality
renal medulla	UBERON:0000362	94.94	gold quality
right lung	UBERON:0002167	94.90	gold quality
inferior vagus X ganglion	UBERON:0005363	94.47	gold quality
right frontal lobe	UBERON:0002810	94.14	gold quality
esophagus mucosa	UBERON:0002469	94.11	gold quality
upper lobe of left lung	UBERON:0008952	93.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.37	gold quality
putamen	UBERON:0001874	93.32	gold quality
amniotic fluid	UBERON:0000173	93.30	gold quality
mucosa of stomach	UBERON:0001199	93.16	gold quality
skin of leg	UBERON:0001511	93.08	gold quality
pons	UBERON:0000988	93.03	gold quality
ileal mucosa	UBERON:0000331	92.73	gold quality
adult mammalian kidney	UBERON:0000082	92.66	gold quality
amygdala	UBERON:0001876	92.64	gold quality
midbrain	UBERON:0001891	92.56	gold quality
substantia nigra	UBERON:0002038	92.51	gold quality
upper lobe of lung	UBERON:0008948	92.37	gold quality
subthalamic nucleus	UBERON:0001906	92.30	silver quality
medulla oblongata	UBERON:0001896	92.24	silver quality
nucleus accumbens	UBERON:0001882	92.03	gold quality
hypothalamus	UBERON:0001898	92.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	351.54
E-ANND-3	yes	10.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting SPNS2, 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-6748-5P	100.00	65.81	1057
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4687-3P	99.48	66.41	968

Literature-anchored findings (GeneRIF, showing 17)

• The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720. (PMID:21084291)
• Spns2 is an S1P transporter in vivo that plays a role in regulation not only of blood S1P but also lymph node and lymph S1P levels and consequently influences lymphocyte trafficking and lymphatic vessel network organization. (PMID:23180825)
• Spns2 plays key roles in regulating the cellular functions in non-small cell lung cancer (NSCLC) cells (PMID:25330231)
• mammals. These findings indicate that Spns2 is required for normal maintenance of the endocochlear potential and hence for normal auditory function, and support a role for S1P signalling in hearing. (PMID:25356849)
• A novel role for Spns2 and S1P1&2 in the activation of p47(phox) and production of reactive oxygen species involved in hyperoxia-mediated lung injury. (PMID:27343196)
• Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development (PMID:27562371)
• In both macrophage and epithelial cell types, Spns2 was also found localized to cytoplasm and the nucleus, in line with a predicted bipartile Nuclear Localization Signal at the position aa282 of the human Spns2 sequence (PMID:29112690)
• our data demonstrate that Spns2 and S1P have a crucial effect on proximal tubular epithelial cells by regulating an inflammatory process and a subsequent fibrotic reaction, and also by influencing other tubular transporters that are involved in the pathophysiology of inflammatory and fibrotic kidney diseases. (PMID:29772789)
• Spinster 2 (SPNS2) was shown to act as a mediator of intracellular sphingosine-1-phosphate (S1P) release and play an important role in the regulation of S1P [Review]. (PMID:30196234)
• SPNS2 promotes the malignancy of colorectal cancer cells via regulating Akt and ERK pathway. (PMID:31206801)
• A possible contribution of the SPNS2 variation to POI was not strictly ruled out, but various data presented in the text including reported association of variations in related gene ALOX12 with menopause-age and role of ALOX12B in atretic bovine follicle formation argue in favor of ALOX12B. It is, therefore, concluded that the mutation in ALOX12B is the likely cause of POI in the pedigree. (PMID:32253496)
• Prognostic Significance of Cytoplasmic SPNS2 Expression in Patients with Oral Squamous Cell Carcinoma. (PMID:33673355)
• Long non-coding RNA HOXA-AS3 facilitates the malignancy in colorectal cancer by miR-4319/SPNS2 axis. (PMID:34671931)
• Iron Deficiency Increases Phosphorylation of SP1 to Upregulate SPNS2 Expression in Hepatocellular Carcinoma. (PMID:35614326)
• Structural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate. (PMID:37224812)
• Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis. (PMID:37358015)
• Spinster homolog 2 reduces malignancies of glioblastoma via PTEN/PI3K/AKT pathway. (PMID:37728571)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spns2	ENSMUSG00000040447
rattus_norvegicus	Spns2	ENSRNOG00000057040
drosophila_melanogaster	spin	FBGN0086676
caenorhabditis_elegans		WBGENE00007549
caenorhabditis_elegans		WBGENE00008033
caenorhabditis_elegans		WBGENE00008598
caenorhabditis_elegans		WBGENE00013739

Paralogs (2): SPNS1 (ENSG00000169682), SPNS3 (ENSG00000182557)

Protein

Protein identifiers

Sphingosine-1-phosphate transporter SPNS2 — Q8IVW8 (reviewed: Q8IVW8)

Alternative names: Protein spinster homolog 2

All UniProt accessions (2): Q8IVW8, I3L4N9

UniProt curated annotations — full annotation on UniProt →

Function. Lipid transporter that specifically mediates export of sphingosine-1-phosphate (sphing-4-enine 1-phosphate, S1P) and sphinganine-1-phosphate in the lymph, thereby playing a role in lymphocyte trafficking. S1P is a bioactive signaling molecule that regulates many physiological processes important for the development and for the immune system. Regulates levels of S1P and the S1P gradient that exists between the high circulating concentrations of S1P and low tissue levels that control lymphocyte trafficking. Required for the egress of T-cells from lymph nodes during an immune response by mediating S1P secretion, which generates a gradient that enables activated T-cells to access lymph. Also required for the egress of immature B-cells from the bone marrow. In contrast, not involved in S1P release from red blood cells. Involved in auditory function. S1P release in the inner ear is required for maintenance of the endocochlear potential in the cochlea. In addition to export, also able to mediate S1P import.

Subcellular location. Cell membrane. Endosome membrane.

Disease relevance. Deafness, autosomal recessive, 115 (DFNB115) [MIM:618457] A form of non-syndromic deafness characterized by severe sensorineural hearing impairment in early childhood. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the major facilitator superfamily. Spinster (TC 2.A.1.49) family.

RefSeq proteins (1): NP_001118230* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011701	MFS	Family
IPR020846	MFS_dom	Domain
IPR036259	MFS_trans_sf	Homologous_superfamily
IPR044770	MFS_spinster-like	Family

Pfam: PF07690

Catalyzed reactions (Rhea), 2 shown:

• sphing-4-enine 1-phosphate(in) = sphing-4-enine 1-phosphate(out) (RHEA:38667)
• sphinganine 1-phosphate(in) = sphinganine 1-phosphate(out) (RHEA:38671)

UniProt features (42 total): helix 19, transmembrane region 11, turn 4, region of interest 2, chain 1, compositionally biased region 1, sequence variant 1, mutagenesis site 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
8RL8	ELECTRON MICROSCOPY	2.79
8RLD	ELECTRON MICROSCOPY	2.84
8EX4	ELECTRON MICROSCOPY	2.93
7YUD	ELECTRON MICROSCOPY	2.98
8KAE	ELECTRON MICROSCOPY	3.18
7YUB	ELECTRON MICROSCOPY	3.22
7YUF	ELECTRON MICROSCOPY	3.29
8EX5	ELECTRON MICROSCOPY	3.47
8JHR	ELECTRON MICROSCOPY	3.52
8EX7	ELECTRON MICROSCOPY	3.53
8EX6	ELECTRON MICROSCOPY	3.54
8G92	ELECTRON MICROSCOPY	3.6
8JHQ	ELECTRON MICROSCOPY	3.6
8QV6	ELECTRON MICROSCOPY	3.68
8QV5	ELECTRON MICROSCOPY	3.69
8RL7	ELECTRON MICROSCOPY	3.76
8RLC	ELECTRON MICROSCOPY	3.9
8EX8	ELECTRON MICROSCOPY	4.17

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IVW8-F1	82.85	0.68

Antibody-complex structures (SAbDab): 8 — 7YUB, 7YUD, 7YUF, 8KAE, 8QV5, 8QV6, 8RL7, 8RLC

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
200	loss of function; does not rescue the cardia bifida phenotype in the morpholino knockdown in zebrafish.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-1430728	Metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 128 (showing top): GOBP_B_CELL_HOMEOSTASIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_SPHINGOLIPID_MEDIATED_SIGNALING_PATHWAY, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_LYMPH_NODE_DEVELOPMENT, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_REGULATION_OF_MONONUCLEAR_CELL_MIGRATION, GOBP_PIGMENTATION, GOBP_LEUKOCYTE_MIGRATION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_BONE_DEVELOPMENT, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_HEMATOPOIETIC_OR_LYMPHOID_ORGAN_DEVELOPMENT

GO Biological Process (15): B cell homeostasis (GO:0001782), regulation of humoral immune response (GO:0002920), sphingosine-1-phosphate receptor signaling pathway (GO:0003376), lipid transport (GO:0006869), sensory perception of sound (GO:0007605), sphingolipid biosynthetic process (GO:0030148), T cell homeostasis (GO:0043029), regulation of eye pigmentation (GO:0048073), lymph node development (GO:0048535), bone development (GO:0060348), lymphocyte migration (GO:0072676), regulation of T cell migration (GO:2000404), lymphocyte homeostasis (GO:0002260), sphingolipid metabolic process (GO:0006665), transmembrane transport (GO:0055085)

GO Molecular Function (2): transmembrane transporter activity (GO:0022857), sphingolipid intramembrane carrier activity (GO:0046624)

GO Cellular Component (4): plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymphocyte homeostasis	2
transport	2
humoral immune response	1
regulation of immune response	1
G protein-coupled receptor signaling pathway	1
sphingolipid mediated signaling pathway	1
lipid localization	1
sensory perception of mechanical stimulus	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
eye pigmentation	1
regulation of developmental pigmentation	1
hematopoietic or lymphoid organ development	1
skeletal system development	1
animal organ development	1
mononuclear cell migration	1
T cell migration	1
regulation of lymphocyte migration	1
leukocyte homeostasis	1
lipid metabolic process	1
cellular process	1
transporter activity	1
transmembrane transport	1
intramembrane lipid carrier activity	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

2086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPNS2	MFSD2B	A6NFX1	990
SPNS2	SPHK1	Q9NYA1	806
SPNS2	S1PR2	O95136	796
SPNS2	SPHK2	Q9NRA0	736
SPNS2	S1PR3	Q99500	669
SPNS2	S1PR5	Q9H228	629
SPNS2	ABCC1	P33527	605
SPNS2	SGPP1	Q9BX95	584
SPNS2	SGPL1	O95470	583
SPNS2	CTSD	P07339	577
SPNS2	S1PR4	O95977	571
SPNS2	ENPP2	Q13822	557
SPNS2	APOM	O95445	535
SPNS2	S1PR1	P21453	478
SPNS2	ABCA1	O95477	469

IntAct

2 interactions, top by confidence:

A	B	Type	Score
SPNS2	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (77): SPNS2 (Affinity Capture-MS), SPNS2 (Synthetic Lethality), SPNS2 (Affinity Capture-RNA), SPNS2 (Positive Genetic), ABHD14B (Affinity Capture-MS), APP (Affinity Capture-MS), KIAA1244 (Affinity Capture-MS), CAND2 (Affinity Capture-MS), CDKAL1 (Affinity Capture-MS), CIAO1 (Affinity Capture-MS), CLPB (Affinity Capture-MS), CNIH4 (Affinity Capture-MS), DCAF8 (Affinity Capture-MS), DDX20 (Affinity Capture-MS), DENND4A (Affinity Capture-MS)

ESM2 similar proteins: A2AKQ0, A2VE55, A5GFZ5, B8B7Q4, F4JN00, O14494, O42602, O60762, O70152, O75352, O88956, P0CK96, P60588, Q15B89, Q1JQ93, Q28HF8, Q2M3R5, Q3ZCD7, Q4L208, Q4R8V4, Q52KD1, Q5PT50, Q5PT53, Q5RDC9, Q5XF09, Q5ZJ75, Q5ZJH8, Q64232, Q6DBP3, Q6DHK8, Q6NMB6, Q6ZL17, Q762D5, Q76EJ3, Q7T0V6, Q8C811, Q8GUJ1, Q8IVW8, Q8R4D1, Q8RXL8

Diamond homologs: A2CER7, A2SWM2, A8WGF7, B0JZE1, P96712, Q08DX7, Q2YDU8, Q5XGK0, Q6ZMD2, Q7ZU13, Q8IVW8, Q8R0G7, Q91VM4, Q9D232, Q9GQQ0, Q9H2V7, O31762, Q796Q1, S0DW25, Q9Y226, B1MCB5, G4MWA9, K5B8L6, O31563, A4WE10, A6TDH1, A7MR37, A8AP55, B5XUP3, B7LNJ1, Q0IZQ3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	106
Likely benign	22
Benign	35

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1704252	NM_001124758.3(SPNS2):c.906G>A (p.Trp302Ter)	Likely pathogenic
521864	NM_001124758.2(SPNS2):c.c.1066_1067delinsT (p.Pro356Cysfs)	Likely pathogenic

SpliceAI

2087 predictions. Top by Δscore:

Variant	Effect	Δscore
17:4525056:GT:G	acceptor_gain	1.0000
17:4525190:GCAG:G	donor_gain	1.0000
17:4525192:AG:A	donor_loss	1.0000
17:4525193:GG:G	donor_loss	1.0000
17:4525194:G:A	donor_loss	1.0000
17:4525195:T:A	donor_loss	1.0000
17:4530630:A:AG	acceptor_gain	1.0000
17:4530631:G:GG	acceptor_gain	1.0000
17:4530631:GT:G	acceptor_gain	1.0000
17:4530783:GGTGA:G	donor_loss	1.0000
17:4530784:G:T	donor_loss	1.0000
17:4530785:T:G	donor_loss	1.0000
17:4531048:TGCA:T	acceptor_loss	1.0000
17:4531050:CAGTG:C	acceptor_loss	1.0000
17:4531051:A:AG	acceptor_gain	1.0000
17:4531051:A:T	acceptor_loss	1.0000
17:4531051:AGT:A	acceptor_gain	1.0000
17:4531051:AGTG:A	acceptor_gain	1.0000
17:4531052:G:GG	acceptor_gain	1.0000
17:4531052:GT:G	acceptor_gain	1.0000
17:4531052:GTG:G	acceptor_gain	1.0000
17:4531052:GTGG:G	acceptor_gain	1.0000
17:4531052:GTGGC:G	acceptor_gain	1.0000
17:4532537:GGCA:G	acceptor_loss	1.0000
17:4532538:GCA:G	acceptor_loss	1.0000
17:4532540:A:C	acceptor_loss	1.0000
17:4532541:GGT:G	acceptor_gain	1.0000
17:4532588:T:TA	acceptor_gain	1.0000
17:4532680:CGAAA:C	donor_gain	1.0000
17:4532681:GAAA:G	donor_gain	1.0000

AlphaMissense

3519 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:4499403:G:T	R119M	0.999
17:4525059:T:C	F147L	0.999
17:4525061:C:A	F147L	0.999
17:4525061:C:G	F147L	0.999
17:4525111:G:C	R164P	0.999
17:4530675:G:A	G206E	0.999
17:4530683:A:C	S209R	0.999
17:4530685:C:A	S209R	0.999
17:4530685:C:G	S209R	0.999
17:4530699:C:A	A214D	0.999
17:4530722:T:C	F222L	0.999
17:4530724:C:A	F222L	0.999
17:4530724:C:G	F222L	0.999
17:4530758:T:C	F234L	0.999
17:4530760:C:A	F234L	0.999
17:4530760:C:G	F234L	0.999
17:4530779:G:C	G241R	0.999
17:4530780:G:A	G241D	0.999
17:4531060:G:C	G245R	0.999
17:4531061:G:A	G245D	0.999
17:4531102:T:A	W259R	0.999
17:4531102:T:C	W259R	0.999
17:4531104:G:C	W259C	0.999
17:4531104:G:T	W259C	0.999
17:4532981:A:C	S314R	0.999
17:4532983:C:A	S314R	0.999
17:4532983:C:G	S314R	0.999
17:4533254:G:A	G367E	0.999
17:4533274:G:A	G374R	0.999
17:4533274:G:C	G374R	0.999

dbSNP variants (sampled 300 via entrez): RS1000028433 (17:4515164 G>C), RS1000084097 (17:4524110 C>T), RS1000178303 (17:4523848 G>A), RS1000246435 (17:4529157 A>T), RS1000315884 (17:4530481 T>G), RS1000336248 (17:4499131 G>A,C,T), RS1000348420 (17:4533506 G>A,C,T), RS1000351900 (17:4532075 GCTAT>G), RS1000407299 (17:4531969 C>A,T), RS1000411597 (17:4498436 A>G), RS1000422995 (17:4534860 C>G,T), RS1000428820 (17:4533088 A>G), RS1000467901 (17:4519394 G>T), RS1000501475 (17:4535607 C>G,T), RS1000543657 (17:4505823 C>T)

Disease associations

OMIM: gene MIM:612584 | disease phenotypes: MIM:618457, MIM:616577

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive 115	Moderate	Autosomal recessive

Mondo (4): hearing loss disorder (MONDO:0005365), hearing loss, autosomal recessive 115 (MONDO:0032762), sensorineural hearing loss disorder (MONDO:0020678), microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (MONDO:0014698)

Orphanet (1): Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (Orphanet:457351)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465270 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC63 Sphingosine phosphate transporters

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
SLF80821178	Inhibition	7.29	pIC50
SLB1122168	Inhibition	7.03	pIC50
SLF1081851	Inhibition	5.71	pIC50

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.85	IC50	1400	nM	CHEMBL5406181
5.55	IC50	2820	nM	CHEMBL5204195

PubChem BioAssay actives

2 with measured affinity, of 19 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[4-(4-decylphenyl)-1-ethylimidazol-2-yl]propan-1-amine;hydrochloride	2036873: Inhibition of Spns2 in human HeLa cells decrease in extracellular S1P level by LC/MS method	ic50	1.4000	uM
3-[4-(4-decylphenyl)-1-methylimidazol-2-yl]propan-1-amine;hydrochloride	2036873: Inhibition of Spns2 in human HeLa cells decrease in extracellular S1P level by LC/MS method	ic50	2.8200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	3
Aflatoxin B1	decreases expression, increases methylation	3
sodium arsenite	increases methylation, decreases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
dihydrosphingosine 1-phosphate	decreases abundance	1
sphingosine 1-phosphate	increases secretion, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
GW 7647	increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	increases expression	1
MT19c compound	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Methotrexate	decreases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Fenofibrate	increases expression	1
Silicon Dioxide	increases expression	1
Sphingolipids	increases abundance	1
Tobacco Smoke Pollution	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5391259	Binding	Inhibition of Spns2 in human HeLa cells assessed as decrease in extracellular S1P level at 3 uM by LC/MS analysis relative to control	Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4WL	LS180-SPNS2-KO-c15	Cancer cell line	Female
CVCL_D4WM	LS180-SPNS2-KO-c19	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss