SLC28A3

Summary

SLC28A3 (solute carrier family 28 member 3, HGNC:16484) is a protein-coding gene on chromosome 9q21.32-q21.33, encoding Solute carrier family 28 member 3 (Q9HAS3). Sodium-dependent, pyrimidine- and purine-selective.

Nucleoside transporters, such as SLC28A3, regulate multiple cellular processes, including neurotransmission, vascular tone, adenosine concentration in the vicinity of cell surface receptors, and transport and metabolism of nucleoside drugs. SLC28A3 shows broad specificity for pyrimidine and purine nucleosides (Ritzel et al., 2001 [PubMed 11032837]).

Source: NCBI Gene 64078 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 98 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001199633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16484
Approved symbol	SLC28A3
Name	solute carrier family 28 member 3
Location	9q21.32-q21.33
Locus type	gene with protein product
Status	Approved
Aliases	CNT3
Ensembl gene	ENSG00000197506
Ensembl biotype	protein_coding
OMIM	608269
Entrez	64078

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000376238, ENST00000495823

RefSeq mRNA: 2 — MANE Select: NM_001199633 NM_001199633, NM_022127

CCDS: CCDS6670

Canonical transcript exons

ENST00000376238 — 18 exons

Exon	Start	End
ENSE00000709477	84290154	84290279
ENSE00000804055	84297221	84297298
ENSE00000804056	84297906	84298019
ENSE00000804057	84299581	84299725
ENSE00000804058	84302200	84302389
ENSE00000804059	84305254	84305345
ENSE00000917637	84279265	84279385
ENSE00000917638	84279975	84280073
ENSE00000917639	84280801	84280882
ENSE00000917640	84285345	84285542
ENSE00000917641	84285943	84286111
ENSE00000917642	84288048	84288178
ENSE00000982982	84294195	84294275
ENSE00000982983	84292668	84292748
ENSE00001469870	84275457	84278344
ENSE00001469935	84340574	84340758
ENSE00003560694	84309629	84309714
ENSE00003597081	84313359	84313454

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 89.55.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0678 / max 56.7136, expressed in 203 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101176	0.5021	109
101174	0.3535	85
101177	0.1120	56
101175	0.0537	37
101178	0.0240	11
101173	0.0225	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	89.55	gold quality
secondary oocyte	CL:0000655	87.16	gold quality
germinal epithelium of ovary	UBERON:0001304	85.80	gold quality
parietal pleura	UBERON:0002400	85.54	gold quality
pancreatic ductal cell	CL:0002079	85.32	silver quality
minor salivary gland	UBERON:0001830	82.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.86	gold quality
gall bladder	UBERON:0002110	81.54	gold quality
body of pancreas	UBERON:0001150	81.47	gold quality
skin of leg	UBERON:0001511	81.42	gold quality
skin of abdomen	UBERON:0001416	80.73	gold quality
pleura	UBERON:0000977	80.13	gold quality
mouth mucosa	UBERON:0003729	79.95	gold quality
zone of skin	UBERON:0000014	79.31	gold quality
gingival epithelium	UBERON:0001949	78.57	gold quality
pancreas	UBERON:0001264	78.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	77.38	gold quality
esophagus squamous epithelium	UBERON:0006920	76.66	gold quality
esophagus mucosa	UBERON:0002469	75.28	gold quality
saliva-secreting gland	UBERON:0001044	75.22	gold quality
nasal cavity mucosa	UBERON:0001826	75.05	gold quality
islet of Langerhans	UBERON:0000006	74.98	gold quality
gingiva	UBERON:0001828	74.65	gold quality
upper leg skin	UBERON:0004262	73.82	gold quality
right uterine tube	UBERON:0001302	73.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.38	gold quality
squamous epithelium	UBERON:0006914	73.17	gold quality
epithelium of esophagus	UBERON:0001976	72.54	gold quality
lower esophagus mucosa	UBERON:0035834	72.16	gold quality
visceral pleura	UBERON:0002401	71.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

105 targeting SLC28A3, 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-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514

Literature-anchored findings (GeneRIF, showing 40)

• hCNT3 gene is evolutionarily conserved with hCNT1 and hCNT2. Physiologically, hCNT3 is a glycoprotein, which transports purine and pyrimidine nucleosides in a Na-dependent manner with high affinities. (PMID:14504928)
• genetic analysis and functional characterization of CNT3 variants suggest that this transporter does not tolerate nonsynonymous changes and is important for human fitness (PMID:15738947)
• examination of single nucleotide polymorphisms in the coding regions of the hCNT3 gene (PMID:15861042)
• hCNT3 possesses two Na+-binding sites, only one of which is shared by H+ (PMID:15870078)
• The effects of cysteine substitution mutants spanning transmembrane domains 11-13 on the transport activity of CNT3 expressed in S. cerevisiae are reported. (PMID:16271041)
• Minimal features required for human CNT3 transport are two hydrogen bond acceptors at 3’-OH and 5’-O and the hydrophobic center occupied by the base ring. (PMID:16446384)
• transcripts for CNT3 protein in human kidneys and in cultured proximal tubule cells suggest involvement of CNT3 in renal handling of nucleosides and nucleoside drugs (PMID:17409283)
• CNT3 was inserted into the apical membrane, thus generating, a transepithelial flux of both nucleosides and nucleoside-derived drugs. (PMID:17412768)
• hCNT2 shares common cation specificity and coupling characteristics with hCNT1, which differ markedly from those of hCNT3. (PMID:17453413)
• This study shows that adenosine elimination on human airway epithelia is mediated by ADA1, CNT2, and CNT3, which constitute important regulators of adenosine-mediated inflammation. (PMID:17696452)
• These data suggest that selected genes of the SLC28 and SLC29 families are not only targets of HIV-1 infection, but might also contribute to the development of adipose tissue alterations leading to lipodystrophy. (PMID:17926640)
• A polymorphic variant of the human concentrative nucleoside transporter, CNT3, is found that severely affects its functionality. (PMID:17993510)
• identified a C-terminal intramembranous cysteine residue of hCNT3 (Cys-561) that reversibly binds the hydrophilic thiol-reactive reagent p-chloromercuribenzene sulfonate (PCMBS) (PMID:18199742)
• a pivotal functional role for Cys-561 in Na+- as well as H+-coupled modes of hCNT3 nucleoside transport (PMID:18621735)
• The isolation and charcterization of an alternatively spliced SLC28A3-related mRNA is reported. (PMID:18827020)
• This evidence suggested that apical CNT3 and basolateral ENT2 are involved in proximal tubular reabsorption of adenosine and some nucleoside drugs and that apical ENT1 is involved in proximal tubular secretion of 2’-deoxyadenosine. (PMID:19297449)
• Pancreatic adenocarcinoma patients with a high expression of hENT1 and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation (PMID:19318496)
• identified residues of functional importance and with a revised 15-TM membrane architecture, suggest a novel membrane-associated topology for a region of the protein (TM 11A) that includes the highly conserved CNT family motif (G/A)XKX(3)NEFVA(Y/M/F) (PMID:19380585)
• identified two conserved pore-lining glutamate residues (Glu-343 and Glu-519) with essential roles in CNT3 Na(+)/nucleoside and H(+)/nucleoside cotransport (PMID:19380587)
• TGF-beta1 acts through activation of ERK1/2 and the small GTPase RhoA to promote plasma membrane trafficking of the hCNT3 protein. (PMID:20172853)
• H+ drives uridine and adenosine transport by hCNT3 with lower affinity but higher maximal transport rate than Na+. (PMID:20495821)
• Acidic and hydrophobic motifs in the N terminus tail of the hCNT3 control ER export and cell surface expression levels in nonpolarized cells, whereas a putative beta-turn domain contributes to hCNT3 polarized surface expression in epithelial cells. (PMID:20643903)
• A genetic variant in SCL28A3 coding for the concentrative nucleoside transporter 3 protects patients with chronic hepatitis C against hemolytic anemia without affecting sustained virological response in hepatitis C virus genotype 1. (PMID:21346688)
• Data show that ENT1, ENT2, ENT4 and CNT3 protein was detected on ovarian carcinoma cells in all effusions, with expression observed in 1-95% of tumor cells. (PMID:21822668)
• association between ribavirin (RBV) serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response (PMID:23195617)
• Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. (PMID:23441093)
• The presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP. (PMID:24300978)
• Genetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of metastatic breast cancer patients treated with paclitaxel-gemcitabine chemotherapy. (PMID:24361227)
• Results show that high CNT3 expression level is associated with overall favorable outcomes and is predictive of clinical outcomes in acute myeloid leukemia patients with t(8;21). (PMID:25955569)
• Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as good candidates for modulatory genes in the auditory system. [meta-analysis] (PMID:26188009)
• The co-expression of galectin-4 and CNT3 proteins is not impaired in inflamed colon from patients with Crohn’s disease, thereby anticipating the integrity of this system for drug targeting. (PMID:26481311)
• CYR61 negatively regulates the nucleoside transporters hENT1 and hCNT3 in pancreatic ductal adenocarcinoma. (PMID:27604902)
• results that validate the newly developed structural homology model of CNT membrane architecture for human CNTs, revealed extended conformationally mobile regions within transport-domain TMs, identified pore-lining residues of functional importance, and provided evidence of an emerging novel elevator-type mechanism of transporter function. (PMID:28385889)
• Data suggest that CNT3 forms a homotrimer in solution and membrane-bound inside cells; the quaternary structure creates an aqueous basin that significantly shortens the substrate translocation distance. (PMID:28661652)
• De novo structure prediction of three N-terminal transmembrane helices of the human concentrative nucleoside transporter 3 (hCNT3) homotrimer belonging to the solute carrier 28 family of transporters (SLC28) using Rosetta program and its Broker protocol. (PMID:28774292)
• human CNT3 homology models generated validate previously published PCMBS SCAM data, and confirm an elevator-type mechanism of membrane transport (PMID:30096006)
• Association of SLC28A3 Gene Expression and CYP2B6*6 Allele with the Response to Fludarabine Plus Cyclophosphamide in Chronic Lymphocytic Leukemia Patients. (PMID:30778771)
• Cryo-EM structure of the human concentrative nucleoside transporter CNT3. (PMID:32776918)
• Characterization of deoxyribonucleoside transport mediated by concentrative nucleoside transporters. (PMID:33910126)
• Gene-Gene Interactions of Gemcitabine Metabolizing-Enzyme Genes hCNT3 and WEE1 for Preventing Severe Gemcitabine-Induced Hematological Toxicity. (PMID:33974709)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Slc28a3	ENSMUSG00000021553
rattus_norvegicus	Slc28a3	ENSRNOG00000018853
drosophila_melanogaster	CNT2	FBGN0025709
drosophila_melanogaster	CNT1	FBGN0033371
caenorhabditis_elegans		WBGENE00017867
caenorhabditis_elegans		WBGENE00017868

Paralogs (2): SLC28A2 (ENSG00000137860), SLC28A1 (ENSG00000156222)

Protein

Protein identifiers

Solute carrier family 28 member 3 — Q9HAS3 (reviewed: Q9HAS3)

Alternative names: Concentrative Na(+)-nucleoside cotransporter 3

All UniProt accessions (1): Q9HAS3

UniProt curated annotations — full annotation on UniProt →

Function. Sodium-dependent, pyrimidine- and purine-selective. Involved in the homeostasis of endogenous nucleosides. Exhibits the transport characteristics of the nucleoside transport system cib or N3 subtype (N3/cib) (with marked transport of both thymidine and inosine). Employs a 2:1 sodium/nucleoside ratio. Transports uridine. Also able to transport gemcitabine, 3’-azido-3’-deoxythymidine (AZT), ribavirin and 3-deazauridine.

Subunit / interactions. Homotrimer.

Subcellular location. Cell membrane Endoplasmic reticulum membrane.

Tissue specificity. Expressed in pancreas, bone marrow, trachea, mammary gland, liver, prostate, and regions of intestine, brain, lung, placenta, testis, kidney, and heart.

Induction. Up-regulated by phorbol myristate acetate (PMA) in HL-60 cells.

Miscellaneous. Exhibits a shorter half-life than isoform 1, degraded via a proteasome-dependent pathway.

Similarity. Belongs to the concentrative nucleoside transporter (CNT) (TC 2.A.41) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HAS3-1	1	yes
Q9HAS3-2	2, hCNT3ins

RefSeq proteins (2): NP_001186562, NP_071410 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002668	CNT_N_dom	Domain
IPR008276	C_nuclsd_transpt	Family
IPR011642	Gate_dom	Domain
IPR011657	CNT_C_dom	Domain
IPR018270	C_nuclsd_transpt_met_bac	Family

Pfam: PF01773, PF07662, PF07670

Catalyzed reactions (Rhea), 6 shown:

• thymidine(out) + 2 Na(+)(out) = thymidine(in) + 2 Na(+)(in) (RHEA:69899)
• cytidine(out) + 2 Na(+)(out) = cytidine(in) + 2 Na(+)(in) (RHEA:69903)
• uridine(out) + 2 Na(+)(out) = uridine(in) + 2 Na(+)(in) (RHEA:69907)
• adenosine(out) + 2 Na(+)(out) = adenosine(in) + 2 Na(+)(in) (RHEA:69911)
• guanosine(out) + 2 Na(+)(out) = guanosine(in) + 2 Na(+)(in) (RHEA:69915)
• inosine(out) + 2 Na(+)(out) = inosine(in) + 2 Na(+)(in) (RHEA:69919)

UniProt features (54 total): sequence variant 15, topological domain 14, transmembrane region 11, sequence conflict 5, compositionally biased region 3, intramembrane region 2, chain 1, region of interest 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6KSW	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAS3-F1	80.28	0.47

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
568	decreased uridine transport. normal localization to the cell membrane.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-83936	Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane
R-HSA-9748787	Azathioprine ADME
R-HSA-9755088	Ribavirin ADME
R-HSA-382551	Transport of small molecules
R-HSA-425397	Transport of vitamins, nucleosides, and related molecules
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-9748784	Drug ADME

MSigDB gene sets: 108 (showing top): GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_XENOBIOTIC_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOMF_NUCLEOBASE_CONTAINING_COMPOUND_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, PETRETTO_LEFT_VENTRICLE_MASS_QTL_CIS_UP, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_TRANSMEMBRANE_TRANSPORT, GOBP_NUCLEOSIDE_TRANSPORT, GOBP_CARBOHYDRATE_DERIVATIVE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, GOCC_CELL_PROJECTION_MEMBRANE, GOCC_APICAL_PART_OF_CELL, GOCC_CLUSTER_OF_ACTIN_BASED_CELL_PROJECTIONS

GO Biological Process (10): xenobiotic metabolic process (GO:0006805), xenobiotic transmembrane transport (GO:0006855), purine nucleoside transmembrane transport (GO:0015860), uridine transmembrane transport (GO:0015862), pyrimidine nucleoside transport (GO:0015864), pyrimidine-containing compound transmembrane transport (GO:0072531), nucleoside transmembrane transport (GO:1901642), purine nucleobase transmembrane transport (GO:1904823), pyrimidine nucleobase transport (GO:0015855), sodium ion transmembrane transport (GO:0035725)

GO Molecular Function (8): purine nucleobase transmembrane transporter activity (GO:0005345), nucleoside:sodium symporter activity (GO:0005415), uridine transmembrane transporter activity (GO:0015213), pyrimidine- and adenosine-specific:sodium symporter activity (GO:0015389), purine-specific nucleoside:sodium symporter activity (GO:0015390), nucleoside transmembrane transporter activity (GO:0005337), protein binding (GO:0005515), symporter activity (GO:0015293)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), brush border membrane (GO:0031526), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Drug ADME	2
Transport of vitamins, nucleosides, and related molecules	1
SLC-mediated transmembrane transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transmembrane transport	3
nucleoside transmembrane transport	3
purine-containing compound transmembrane transport	2
nucleoside transport	2
solute:sodium symporter activity	2
metabolic process	1
cellular response to xenobiotic stimulus	1
xenobiotic transport	1
pyrimidine nucleoside transport	1
pyrimidine-containing compound transmembrane transport	1
nitrogen compound transport	1
purine nucleobase transport	1
nucleobase transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
nucleobase transmembrane transporter activity	1
purine nucleobase transmembrane transport	1
nucleoside transmembrane transporter activity	1
pyrimidine nucleoside transmembrane transporter activity	1
uridine transmembrane transport	1
purine nucleobase transmembrane transporter activity	1
pyrimidine nucleobase transmembrane transporter activity	1
nucleoside:sodium symporter activity	1
nucleobase:monoatomic cation symporter activity	1
nucleobase-containing compound transmembrane transporter activity	1
carbohydrate derivative transmembrane transporter activity	1
binding	1
secondary active transmembrane transporter activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
brush border	1
apical plasma membrane	1
cell projection membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC28A3	SLC29A2	Q14542	892
SLC28A3	SLC29A1	Q99808	892
SLC28A3	SLC29A3	Q9BZD2	755
SLC28A3	DCK	P27707	700
SLC28A3	SLC29A4	Q7RTT9	696
SLC28A3	CDA	P32320	624
SLC28A3	CBR3	O75828	551
SLC28A3	ABCC5	O15440	526
SLC28A3	NT5C2	P49902	506
SLC28A3	SLC22A7	Q9Y694	504
SLC28A3	SLC31A1	O15431	504
SLC28A3	GART	P22102	486
SLC28A3	TYMS	P04818	485
SLC28A3	ITPA	Q9BY32	484
SLC28A3	UGT1A6	P19224	480
SLC28A3	DCTD	P32321	480

IntAct

6 interactions, top by confidence:

A	B	Type	Score
SLC28A3	LGALS4	psi-mi:“MI:0915”(physical association)	0.600
SLC28A3	LGALS4	psi-mi:“MI:0403”(colocalization)	0.600
SLC28A3	IGKC	psi-mi:“MI:0914”(association)	0.350
SLC28A3	CLGN	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): SLC28A3 (Affinity Capture-MS), SLC28A3 (Affinity Capture-MS), ACBD3 (Affinity Capture-MS), ARMCX3 (Affinity Capture-MS), B3GALT6 (Affinity Capture-MS), CANX (Affinity Capture-MS), CDKAL1 (Affinity Capture-MS), CLGN (Affinity Capture-MS), COMTD1 (Affinity Capture-MS), EPDR1 (Affinity Capture-MS), HADHA (Affinity Capture-MS), HADHB (Affinity Capture-MS), MAVS (Affinity Capture-MS), PHB (Affinity Capture-MS), PPIB (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KQY6, A0A6I8PMZ8, A0JPN2, A4IGY6, A5D7L5, A7T1N0, B3DHU2, O43868, O75899, O88871, O94402, P04919, P0DX17, P23562, P26432, P26433, P48764, P55205, Q08E40, Q0DHJ5, Q0DWA9, Q0VCH8, Q15043, Q28C60, Q4VAE3, Q504Y0, Q5FVQ0, Q5FWH7, Q5RAB7, Q5Z413, Q6DCK1, Q6L8F3, Q6PI78, Q75N73, Q78IQ7, Q80T41, Q8K596, Q8VIH3, Q8W469, Q91W10

Diamond homologs: E9PXX9, O00337, O25792, O32115, O43868, O62667, O88627, P33021, P33024, P44742, Q62674, Q62773, Q8VIH3, Q9ERH8, Q9HAS3, Q9MZT2, Q9UA35, P39141, P0AFF2, P0AFF3, P42312

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2521 predictions. Top by Δscore:

Variant	Effect	Δscore
9:84278340:CAGTG:C	acceptor_gain	1.0000
9:84278342:GTG:G	acceptor_gain	1.0000
9:84279261:ATAC:A	donor_loss	1.0000
9:84279262:TACC:T	donor_loss	1.0000
9:84279386:C:CC	acceptor_gain	1.0000
9:84280074:C:CC	acceptor_gain	1.0000
9:84280799:A:AC	donor_gain	1.0000
9:84280800:C:CT	donor_gain	1.0000
9:84280878:CGAAT:C	acceptor_gain	1.0000
9:84280880:AATCT:A	acceptor_loss	1.0000
9:84280882:TC:T	acceptor_loss	1.0000
9:84280883:C:A	acceptor_loss	1.0000
9:84280884:T:G	acceptor_loss	1.0000
9:84285539:TTAG:T	acceptor_gain	1.0000
9:84285543:C:CC	acceptor_gain	1.0000
9:84290077:A:T	acceptor_gain	1.0000
9:84292666:A:AC	donor_gain	1.0000
9:84292667:C:CC	donor_gain	1.0000
9:84292667:CTTGT:C	donor_gain	1.0000
9:84292744:CCAAC:C	acceptor_gain	1.0000
9:84292745:CAAC:C	acceptor_gain	1.0000
9:84292745:CAACC:C	acceptor_gain	1.0000
9:84292749:C:CC	acceptor_gain	1.0000
9:84292750:T:C	acceptor_loss	1.0000
9:84294189:CAGTA:C	donor_loss	1.0000
9:84294190:AGTAC:A	donor_loss	1.0000
9:84294191:GTACC:G	donor_loss	1.0000
9:84294192:TACCT:T	donor_loss	1.0000
9:84294193:ACCTT:A	donor_loss	1.0000
9:84294271:AGGAC:A	acceptor_gain	1.0000

AlphaMissense

4537 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:84280011:C:A	G598W	0.997
9:84285415:A:G	L526P	0.997
9:84280841:A:C	F563L	0.996
9:84280841:A:T	F563L	0.996
9:84280843:A:G	F563L	0.996
9:84285457:C:T	G512D	0.994
9:84280851:A:G	L560P	0.993
9:84280010:C:T	G598E	0.992
9:84280854:G:T	A559D	0.992
9:84285427:G:T	A522D	0.992
9:84280011:C:G	G598R	0.991
9:84280011:C:T	G598R	0.991
9:84280851:A:T	L560H	0.991
9:84280855:C:G	A559P	0.991
9:84285450:C:A	K514N	0.991
9:84285450:C:G	K514N	0.991
9:84290181:G:C	S374R	0.991
9:84290181:G:T	S374R	0.991
9:84290183:T:G	S374R	0.991
9:84279982:G:C	C607W	0.990
9:84285469:G:T	A508D	0.990
9:84285536:A:G	C486R	0.990
9:84288153:G:T	A392E	0.990
9:84288162:A:G	L389S	0.990
9:84280835:A:C	N565K	0.989
9:84280835:A:T	N565K	0.989
9:84288144:A:C	M395R	0.989
9:84288147:A:T	V394D	0.989
9:84288154:C:G	A392P	0.989
9:84292681:A:T	I337K	0.989

dbSNP variants (sampled 300 via entrez): RS1000016072 (9:84314516 GC>G), RS1000033216 (9:84281416 TCAC>T), RS1000072622 (9:84310521 C>T), RS1000074937 (9:84302517 C>T), RS1000107847 (9:84324645 G>A), RS1000112307 (9:84303878 A>G), RS1000185384 (9:84334226 G>A), RS1000218627 (9:84275219 T>A), RS1000244089 (9:84368107 T>C), RS1000253990 (9:84286788 C>A), RS1000254974 (9:84288776 AC>A), RS1000271482 (9:84362697 T>C), RS1000285581 (9:84357509 G>A,C), RS1000314932 (9:84363428 G>A), RS1000379918 (9:84368452 C>T)

Disease associations

OMIM: gene MIM:608269 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000635_17	Response to statin therapy	6.000000e-06
GCST001762_921	Obesity-related traits	4.000000e-06
GCST002114_2	Molar-incisor hypomineralization	2.000000e-06
GCST002337_138	Amyotrophic lateral sclerosis (sporadic)	8.000000e-06
GCST002805_9	Body mass index	3.000000e-07
GCST003784_11	Multiple system atrophy	8.000000e-06
GCST003993_31	Menarche (age at onset)	1.000000e-11
GCST004583_2	Waist-to-hip circumference ratio (recreational physical activity interaction)	9.000000e-06
GCST004904_62	Body mass index	1.000000e-08
GCST004904_81	Body mass index	1.000000e-09
GCST005648_5	Serum metabolite concentrations in chronic kidney disease	3.000000e-09
GCST007292_18	Diabetic retinopathy (all NPDR and PDR)	2.000000e-07
GCST007327_158	Smoking status (ever vs never smokers)	3.000000e-11
GCST007829_1	Systolic blood pressure	9.000000e-08
GCST008179_23	Moderate-to-late spontaneous preterm birth	7.000000e-06
GCST008810_27	Smoking initiation (ever regular vs never regular)	5.000000e-10
GCST010219_12	Attention deficit hyperactivity disorder (inattention symptoms)	7.000000e-07
GCST010273_4	Gout (normal type)	3.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005321	molar-incisor hypomineralization
EFO:0005937	longitudinal BMI measurement
EFO:0004703	age at menarche
EFO:0004343	waist-hip ratio
EFO:0004340	body mass index
EFO:0004318	smoking behavior
EFO:0006944	systolic blood pressure change measurement
EFO:0006917	spontaneous preterm birth
EFO:0005670	smoking initiation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5707 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 325,018 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL477	ADENOSINE	4	222,014
CHEMBL100259	URIDINE	3	103,004

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4877847	Toxicity	4	anthracyclines and related substances	Neoplasms
rs7853758	Toxicity	2B	anthracyclines and related substances;daunorubicin;doxorubicin	Cardiotoxicity
rs7867504	Other	3	gemcitabine	Neoplasms
rs885004	Toxicity	3	anthracyclines and related substances	Neoplasms

PharmGKB variants

14 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs885004	SLC28A3	3	2.00	1	anthracyclines and related substances
rs4305983	SLC28A3		0.00	0
rs4588940	SLC28A3		0.00	0
rs4877831	SLC28A3		0.00	0
rs4877847	SLC28A3	4	-1.25	1	anthracyclines and related substances
rs7035753	SLC28A3		0.00	0
rs7043257	SLC28A3		0.00	0
rs7853758	SLC28A3	2B	10.50	1	anthracyclines and related substances;daunorubicin;doxorubicin
rs7867504	SLC28A3	3	0.00	1	gemcitabine
rs10868138	SLC28A3		0.00	0
rs17087144	SLC28A3		0.00	0
rs17428030	SLC28A3		0.00	0
rs17343066	SLC28A3		0.00	0
rs11140490	SLC28A3		0.00	0

PharmGKB dosing guidelines

1 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPNDS	daunorubicin;doxorubicin	Annotation of CPNDS Guideline for daunorubicin, doxorubicin and RARG, SLC28A3, UGT1A6		yes

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC28 family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 16 [PMID: 19097778]	Inhibition	5.54	pKi

ChEMBL bioactivities

5 potent at pChembl≥5 of 14 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.68	Ki	2100	nM	ADENOSINE
5.54	Ki	2880	nM	CHEMBL482331
5.48	IC50	3300	nM	ADENOSINE
5.47	Ki	3400	nM	URIDINE
5.27	IC50	5400	nM	URIDINE

PubChem BioAssay actives

5 with measured affinity, of 30 total; 3 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
Adenosine	1222909: Binding affinity to recombinant human CNT3 expressed in Saccharomyces cerevisiae assessed as inhibition of [3H]-uridine transport after 5 mins by scintillation counting analysis	ki	2.1000	uM
1-[2-[(2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one	370698: Binding affinity to human recombinant CNT3 expressed in pig PK15NTD cells assessed as [3H]uridine uptake by beta-scintillation counter	ki	2.8800	uM
Uridine	1222909: Binding affinity to recombinant human CNT3 expressed in Saccharomyces cerevisiae assessed as inhibition of [3H]-uridine transport after 5 mins by scintillation counting analysis	ki	3.4000	uM

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
domiphen	affects response to substance	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
sulforaphane	decreases expression	1
CGP 52608	affects binding, increases reaction	1
3-iodothyronamine	affects uptake	1
abrine	increases expression	1
prothioconazole	increases expression	1
(+)-JQ1 compound	decreases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cholesterol	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Zidovudine	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 2 admet, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3528994	ADMET	Binding affinity to recombinant human CNT3 expressed in Saccharomyces cerevisiae assessed as inhibition of [3H]-uridine transport after 5 mins by scintillation counting analysis	Transport of A1 adenosine receptor agonist tecadenoson by human and mouse nucleoside transporters: evidence for blood-brain barrier transport by murine equilibrative nucleoside transporter 1 mENT1. — Drug Metab Dispos
CHEMBL957102	Binding	Binding affinity to human recombinant CNT3 expressed in pig PK15NTD cells assessed as [3H]uridine uptake by beta-scintillation counter	Synthesis and biological evaluation of phloridzin analogs as human concentrative nucleoside transporter 3 (hCNT3) 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_D4VM	LS180-SLC28A3-KO-c13	Cancer cell line	Female
CVCL_D4VN	LS180-SLC28A3-KO-c19	Cancer cell line	Female

Clinical trials (associated diseases)

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