SLC13A3

Summary

SLC13A3 (solute carrier family 13 member 3, HGNC:14430) is a protein-coding gene on chromosome 20q13.12, encoding Na(+)/dicarboxylate cotransporter 3 (Q8WWT9). High-affinity sodium-dicarboxylate cotransporter that accepts a range of substrates with 4-6 carbon atoms, such as the citric acid cycle intermediates succinate and alpha-ketoglutarate (2-oxoglutarate), as well as other compounds including N-acetyl-L-aspartate.

Mammalian sodium-dicarboxylate cotransporters transport succinate and other Krebs cycle intermediates. They fall into 2 categories based on their substrate affinity: low affinity and high affinity. Both the low- and high-affinity transporters play an important role in the handling of citrate by the kidneys. The protein encoded by this gene represents the high-affinity form. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, although the full-length nature of some of them have not been characterized yet.

Source: NCBI Gene 64849 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate (Strong, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 245 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes
• MANE Select transcript: NM_022829

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14430
Approved symbol	SLC13A3
Name	solute carrier family 13 member 3
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	NADC3, SDCT2
Ensembl gene	ENSG00000158296
Ensembl biotype	protein_coding
OMIM	606411
Entrez	64849

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000279027, ENST00000290317, ENST00000372121, ENST00000413164, ENST00000417157, ENST00000420568, ENST00000450298, ENST00000464518, ENST00000468915, ENST00000472148, ENST00000495082

RefSeq mRNA: 5 — MANE Select: NM_022829 NM_001011554, NM_001193339, NM_001193340, NM_001193342, NM_022829

CCDS: CCDS13400, CCDS42886, CCDS54469, CCDS54470

Canonical transcript exons

ENST00000279027 — 13 exons

Exon	Start	End
ENSE00000512850	46566229	46566390
ENSE00000662660	46563414	46563551
ENSE00001123042	46575573	46575685
ENSE00001926151	46557828	46560198
ENSE00003489255	46651311	46651459
ENSE00003548277	46613460	46613725
ENSE00003565564	46610446	46610609
ENSE00003576904	46589160	46589255
ENSE00003590813	46588059	46588163
ENSE00003632133	46592404	46592529
ENSE00003666210	46599971	46600037
ENSE00003679027	46596157	46596342
ENSE00003788664	46583572	46583669

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 95.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.0505 / max 638.0118, expressed in 1053 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187580	2.4535	921
187579	1.7145	173
187574	0.4258	140
187572	0.1839	63
187578	0.1126	56
187577	0.0820	43
187573	0.0494	31
187576	0.0166	6
187575	0.0122	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nephron tubule	UBERON:0001231	95.88	gold quality
adult mammalian kidney	UBERON:0000082	95.69	gold quality
kidney epithelium	UBERON:0004819	95.07	gold quality
metanephric glomerulus	UBERON:0004736	95.05	gold quality
renal glomerulus	UBERON:0000074	94.39	gold quality
oocyte	CL:0000023	93.80	gold quality
adult organism	UBERON:0007023	92.75	gold quality
kidney	UBERON:0002113	91.73	gold quality
secondary oocyte	CL:0000655	90.79	gold quality
olfactory bulb	UBERON:0002264	89.18	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.74	gold quality
corpus callosum	UBERON:0002336	86.59	gold quality
spinal cord	UBERON:0002240	86.42	gold quality
cortex of kidney	UBERON:0001225	86.36	gold quality
type B pancreatic cell	CL:0000169	85.62	gold quality
metanephros	UBERON:0000081	84.15	gold quality
right lobe of liver	UBERON:0001114	83.77	gold quality
placenta	UBERON:0001987	83.35	gold quality
inferior olivary complex	UBERON:0002127	83.15	gold quality
substantia nigra	UBERON:0002038	83.03	gold quality
renal medulla	UBERON:0000362	83.00	gold quality
pigmented layer of retina	UBERON:0001782	82.39	gold quality
retina	UBERON:0000966	82.37	gold quality
midbrain	UBERON:0001891	82.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.33	gold quality
nasal cavity epithelium	UBERON:0005384	81.93	silver quality
liver	UBERON:0002107	81.64	gold quality
triceps brachii	UBERON:0001509	81.48	gold quality
buccal mucosa cell	CL:0002336	81.26	silver quality
gluteal muscle	UBERON:0002000	81.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1815.26
E-CURD-119	yes	1766.35
E-ANND-3	yes	9.37

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PITX2

miRNA regulators (miRDB)

121 targeting SLC13A3, 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-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674

Literature-anchored findings (GeneRIF, showing 12)

• The narrow substrate specificity prevents interaction of drugs with dicarboxylate-like structure with hNaDC-3 and ensures sufficient support of the proximal tubule cells with alpha-ketoglutarate for anion secretion via organic anion transporter 1 or 3. (PMID:15561973)
• We provide direct evidence of the localization of NaDC3 at the basolateral membrane of human renal proximal tubule cells and identify a di-hydrophobic amino acid motif VW as basolateral localization signal in the N-terminal cytoplasmic domain of NaDC3. (PMID:16331647)
• NaDC3 promotes cellular senescence probably by inhibiting NAD(+)-dependent SIRT1. (PMID:20813124)
• The data 1) reveal alpha-ketoglutarate as a common high-affinity substrate of NaDC3, OAT1, and OAT3 (PMID:21865262)
• The results indicate that SLC13A3 is a direct downstream target of PITX2 transcriptional regulation and that levels of PITX2 and SLC13A3 modulate responses to oxidative stress in ocular cells. (PMID:21873665)
• study concludes NaDC3 present at the basolateral membrane of proximal tubule cells mediates sodium-dependent glutathione (GSH) uptake; the kinetic data show that NaDC3 is a low-affinity GSH transporter (PMID:24247155)
• In a study addressing genetic, social, and environmental contributors of chronic kidney disease with tubulointerstitial damages in Sri Lanka, SNP rs6066043 of SLC13A3 was found attributable risk of 50%. (PMID:24351856)
• OAT1 and NaDC3 in the basolateral membrane and OAT4 in the luminal membrane of proximal tubule cells are responsible for the avid renal secretion of N-carbamoylglutamate. (PMID:25354943)
• NaDC3-related immunostaining was detected in the basolateral membrane of proximal tubules and in the basolateral membrane and/or luminal membrane of principal cells in connecting segments and collecting ducts (PMID:27053689)
• Association of Single Nucleotide Polymorphisms in KCNA10 and SLC13A3 Genes with the Susceptibility to Chronic Kidney Disease of Unknown Etiology in Central Indian Patients. (PMID:36696070)
• Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability. (PMID:37794328)
• SLC13A3 is a major effector downstream of activated beta-catenin in liver cancer pathogenesis. (PMID:39215042)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc13a3	ENSDARG00000069478
mus_musculus	Slc13a3	ENSMUSG00000018459
rattus_norvegicus	Slc13a3	ENSRNOG00000019118
drosophila_melanogaster	CG7309	FBGN0032314
drosophila_melanogaster	Indy	FBGN0036816
drosophila_melanogaster	CG33934	FBGN0064119
drosophila_melanogaster	Indy-2	FBGN0260466
caenorhabditis_elegans		WBGENE00003517
caenorhabditis_elegans		WBGENE00003518
caenorhabditis_elegans		WBGENE00003519
caenorhabditis_elegans		WBGENE00007138

Paralogs (5): SLC13A2 (ENSG00000007216), SLC13A1 (ENSG00000081800), OCA2 (ENSG00000104044), SLC13A5 (ENSG00000141485), SLC13A4 (ENSG00000164707)

Protein

Protein identifiers

Na(+)/dicarboxylate cotransporter 3 — Q8WWT9 (reviewed: Q8WWT9)

Alternative names: Na(+)-coupled carboxylate transporter 3, Sodium-dependent high-affinity dicarboxylate transporter 2, Solute carrier family 13 member 3

All UniProt accessions (6): Q8WWT9, A0A0A0MRQ6, C9J4A3, C9J7L4, H7C0C8, X6RDV4

UniProt curated annotations — full annotation on UniProt →

Function. High-affinity sodium-dicarboxylate cotransporter that accepts a range of substrates with 4-6 carbon atoms, such as the citric acid cycle intermediates succinate and alpha-ketoglutarate (2-oxoglutarate), as well as other compounds including N-acetyl-L-aspartate. Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic. Can transport citrate in a Na(+)-dependent manner, recognizing the divalent form of citrate rather than the trivalent form which is normally found in blood. Imports itaconate in hepatocytes leading to activation of TFEB-dependent lysosomal biogenesis involved in antibacterial innate immune response.

Subunit / interactions. Homodimer; the dimer shifts between outward and inward conformations to generate an elevator-type movement for substrate transport.

Subcellular location. Cell membrane.

Tissue specificity. Expression is highest in kidney. Detected in placenta, brain, liver and pancreas.

Disease relevance. Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate (ARLIAK) [MIM:618384] An autosomal recessive disorder characterized by acute, reversible neurological deterioration during febrile illness. Patients exhibit reversible leukoencephalopathy and increased urinary excretion of alpha-ketoglutarate. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Li(+) decreases succinate transport in the presence of Na(+).

Domain organisation. The SNT motifs and TXP motif are essential for substrate recognition.

Similarity. Belongs to the SLC13A/DASS transporter (TC 2.A.47) family. NADC subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q8WWT9-1	1	yes
Q8WWT9-2	2
Q8WWT9-3	3
Q8WWT9-4	4
Q8WWT9-5	5
Q8WWT9-6	6

RefSeq proteins (5): NP_001011554, NP_001180268, NP_001180269, NP_001180271, NP_073740* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001898	SLC13A/DASS	Family

Pfam: PF00939

Catalyzed reactions (Rhea), 9 shown:

• succinate(out) + 3 Na(+)(out) = succinate(in) + 3 Na(+)(in) (RHEA:71919)
• fumarate(out) + 3 Na(+)(out) = fumarate(in) + 3 Na(+)(in) (RHEA:71931)
• 2-oxoglutarate(out) + 3 Na(+)(out) = 2-oxoglutarate(in) + 3 Na(+)(in) (RHEA:71939)
• N-acetyl-L-aspartate(out) + 3 Na(+)(out) = N-acetyl-L-aspartate(in) + 3 Na(+)(in) (RHEA:71947)
• glutarate(out) + 3 Na(+)(out) = glutarate(in) + 3 Na(+)(in) (RHEA:71955)
• 2,2-dimethylsuccinate(out) + 3 Na(+)(out) = 2,2-dimethylsuccinate(in) + 3 Na(+)(in) (RHEA:72287)
• 2,3-dimethylsuccinate(out) + 3 Na(+)(out) = 2,3-dimethylsuccinate(in) + 3 Na(+)(in) (RHEA:72291)
• malate(out) + 3 Na(+)(out) = malate(in) + 3 Na(+)(in) (RHEA:72295)
• itaconate(out) + 3 Na(+)(out) = itaconate(in) + 3 Na(+)(in) (RHEA:82295)

UniProt features (90 total): helix 30, topological domain 14, transmembrane region 11, splice variant 7, turn 6, binding site 4, strand 4, short sequence motif 3, sequence conflict 3, intramembrane region 2, glycosylation site 2, sequence variant 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8UVC	ELECTRON MICROSCOPY	2.09
8UVD	ELECTRON MICROSCOPY	2.16
8UVF	ELECTRON MICROSCOPY	2.17
8UVI	ELECTRON MICROSCOPY	2.53
8UVE	ELECTRON MICROSCOPY	2.6
8UVG	ELECTRON MICROSCOPY	2.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWT9-F1	81.62	0.53

Functional residue map

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

Ligand- & substrate-binding residues (4): 144; 253; 527; 528

Glycosylation sites (2): 586, 596

Mutagenesis-validated functional residues (1):

Position	Phenotype
93	impairs succinate transport.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9955298	SLC-mediated transport of organic anions
R-HSA-433137	Sodium-coupled sulphate, di- and tri-carboxylate transporters
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 200 (showing top): GOBP_CIRCULATORY_SYSTEM_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, FOSTER_TOLERANT_MACROPHAGE_DN, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_SULFUR_COMPOUND_TRANSPORT, GOBP_DICARBOXYLIC_ACID_TRANSPORT, CHIANG_LIVER_CANCER_SUBCLASS_INTERFERON_DN, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, GOBP_LIPID_LOCALIZATION, GOBP_TRANSMEMBRANE_TRANSPORT

GO Biological Process (11): dicarboxylic acid transport (GO:0006835), lipid transport (GO:0006869), citrate transport (GO:0015746), glutathione transmembrane transport (GO:0034775), succinate transmembrane transport (GO:0071422), transport across blood-brain barrier (GO:0150104), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), alpha-ketoglutarate transport (GO:0015742), sodium ion transmembrane transport (GO:0035725), transmembrane transport (GO:0055085)

GO Molecular Function (11): dicarboxylic acid transmembrane transporter activity (GO:0005310), citrate transmembrane transporter activity (GO:0015137), alpha-ketoglutarate transmembrane transporter activity (GO:0015139), succinate transmembrane transporter activity (GO:0015141), high-affinity sodium:dicarboxylate symporter activity (GO:0015362), sodium:dicarboxylate symporter activity (GO:0017153), glutathione transmembrane transporter activity (GO:0034634), protein binding (GO:0005515), symporter activity (GO:0015293), solute:sodium symporter activity (GO:0015370), transmembrane transporter activity (GO:0022857)

GO Cellular Component (4): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
SLC-mediated transport of inorganic anions	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
dicarboxylic acid transport	2
dicarboxylic acid transmembrane transporter activity	2
carboxylic acid transport	1
lipid localization	1
tricarboxylic acid transport	1
glutathione transport	1
tripeptide transmembrane transport	1
succinate transport	1
carboxylic acid transmembrane transport	1
vascular transport	1
metal ion transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
cellular process	1
carboxylic acid transmembrane transporter activity	1
tricarboxylic acid transmembrane transporter activity	1
citrate transport	1
alpha-ketoglutarate transport	1
C4-dicarboxylate transmembrane transporter activity	1
succinate transmembrane transport	1
sodium:dicarboxylate symporter activity	1
organic acid:sodium symporter activity	1
glutathione transmembrane transport	1
tripeptide transmembrane transporter activity	1
modified amino acid transmembrane transporter activity	1
sulfur compound transmembrane transporter activity	1
binding	1
secondary active transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
solute:monoatomic cation symporter activity	1
transporter activity	1
transmembrane transport	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1026 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC13A3	SLC26A2	P50443	788
SLC13A3	SLC15A5	A6NIM6	734
SLC13A3	SLC22A8	Q8TCC7	637
SLC13A3	SLC22A6	Q4U2R8	613
SLC13A3	SLC26A3	P40879	609
SLC13A3	SLC22A11	Q9NSA0	502
SLC13A3	SLC5A12	Q1EHB4	500
SLC13A3	SLC22A7	Q9Y694	500
SLC13A3	SLC17A1	Q14916	473
SLC13A3	SLC17A3	O00476	471
SLC13A3	SLC25A1	P53007	463
SLC13A3	SLC5A8	Q8N695	432
SLC13A3	SLC13A2	Q13183	431
SLC13A3	SLC22A9	Q8IVM8	423
SLC13A3	SLC22A13	Q9Y226	422

IntAct

30 interactions, top by confidence:

A	B	Type	Score
SLC13A3	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
CYB5R3	SLC13A3	psi-mi:“MI:0915”(physical association)	0.560
CISD2	SLC13A3	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	SLC13A3	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	SLC13A3	psi-mi:“MI:0915”(physical association)	0.560
SLC13A3	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
GPX8	SLC13A3	psi-mi:“MI:0915”(physical association)	0.560
LEUTX	SLC13A3	psi-mi:“MI:0915”(physical association)	0.560
SLC13A3	RMDN3	psi-mi:“MI:0915”(physical association)	0.560
SLC13A3	TSC2	psi-mi:“MI:0915”(physical association)	0.370
SLC13A3	GOLIM4	psi-mi:“MI:0914”(association)	0.350
SLC13A3	CREB3L1	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	CYB5R3	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	CISD2	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	ERGIC3	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	RMDN3	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	FAM209A	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	ARL13B	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	GPX8	psi-mi:“MI:0915”(physical association)	0.000
SLC13A3	LEUTX	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (51): SLC13A3 (Two-hybrid), SLC13A3 (Two-hybrid), SLC13A3 (Two-hybrid), SLC13A3 (Two-hybrid), SLC13A3 (Two-hybrid), SLC13A3 (Two-hybrid), SLC13A3 (Two-hybrid), GPX8 (Two-hybrid), ARL13B (Two-hybrid), LEUTX (Two-hybrid), SLC13A3 (Two-hybrid), SLC13A3 (Positive Genetic), ALYREF (Affinity Capture-MS), AUP1 (Affinity Capture-MS), BCAP31 (Affinity Capture-MS)

ESM2 similar proteins: A0A6P3HVI0, A2VDL4, A4IHB9, D3ZJ25, E7EXX2, O00341, O19105, O35544, O35874, O35921, O43511, O54902, O57321, P24942, P31596, P31597, P43003, P43004, P43005, P43006, P43007, P46411, P48664, P49281, P49282, P51906, P51907, P51912, P55012, P56564, Q10901, Q15758, Q25605, Q4R8W8, Q5BKR2, Q5R6B8, Q5R839, Q86UD5, Q8BJA2, Q8IVJ1

Diamond homologs: P0AFU2, P0AFU3, P32739, P46556, P70545, Q13183, Q21339, Q28615, Q49YW0, Q67BT3, Q86YT5, Q8CJ44, Q8WWT9, Q91Y63, Q93655, Q9ES88, Q9VDQ0, Q9VVT2, Q9Z0Z5, P39535, Q07782, Q9BZW2, Q9JHI4, O59712, P25360, P72958, Q2FFH9, Q2FWY4, Q2YU56, Q5HEK4, Q6G816, Q6GFE0, Q7A4P8, Q8LG88, Q8NVS5, Q99SX1, Q9UKG4, P86282, Q57486, Q58086

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	131
Likely benign	77
Benign	18

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
625424	NM_022829.6(SLC13A3):c.761C>A (p.Ala254Asp)	Pathogenic
625425	NM_022829.6(SLC13A3):c.1642G>A (p.Gly548Ser)	Pathogenic
2502844	NM_022829.6(SLC13A3):c.1478C>T (p.Pro493Leu)	Likely pathogenic
3587278	NM_022829.6(SLC13A3):c.795-2_796del	Likely pathogenic

SpliceAI

3041 predictions. Top by Δscore:

Variant	Effect	Δscore
20:46563409:CTCA:C	donor_loss	1.0000
20:46563410:TCA:T	donor_loss	1.0000
20:46563411:CACCA:C	donor_loss	1.0000
20:46563412:ACCAT:A	donor_loss	1.0000
20:46563604:C:CT	acceptor_gain	1.0000
20:46566223:CCTCA:C	donor_loss	1.0000
20:46566224:CTCA:C	donor_loss	1.0000
20:46566225:TCACC:T	donor_loss	1.0000
20:46566226:CACCA:C	donor_loss	1.0000
20:46566227:A:AC	donor_gain	1.0000
20:46566228:C:CC	donor_gain	1.0000
20:46566228:CCAG:C	donor_gain	1.0000
20:46576776:T:TA	donor_gain	1.0000
20:46589158:A:AC	donor_gain	1.0000
20:46589159:C:CC	donor_gain	1.0000
20:46596257:T:TA	donor_gain	1.0000
20:46599970:CG:C	donor_gain	1.0000
20:46610441:CTCA:C	donor_loss	1.0000
20:46610442:TCACC:T	donor_loss	1.0000
20:46610444:A:AT	donor_loss	1.0000
20:46610463:T:A	donor_gain	1.0000
20:46610565:C:CT	acceptor_gain	1.0000
20:46613455:CTTA:C	donor_loss	1.0000
20:46613457:TA:T	donor_loss	1.0000
20:46651305:CGTTA:C	donor_loss	1.0000
20:46651306:GTTAC:G	donor_loss	1.0000
20:46651307:TTACC:T	donor_loss	1.0000
20:46651308:TA:T	donor_loss	1.0000
20:46651309:ACCTT:A	donor_loss	1.0000
20:46651310:C:A	donor_loss	1.0000

AlphaMissense

3929 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:46563456:G:C	N530K	0.999
20:46563456:G:T	N530K	0.999
20:46592492:A:G	W278R	0.999
20:46592492:A:T	W278R	0.999
20:46596196:C:T	G252D	0.999
20:46596197:C:G	G252R	0.999
20:46596217:C:T	G245E	0.999
20:46596222:A:C	S243R	0.999
20:46596222:A:T	S243R	0.999
20:46596224:T:G	S243R	0.999
20:46610566:A:G	W141R	0.999
20:46610566:A:T	W141R	0.999
20:46563444:G:C	F534L	0.998
20:46563444:G:T	F534L	0.998
20:46563446:A:G	F534L	0.998
20:46563448:G:T	A533D	0.998
20:46563475:G:T	P524Q	0.998
20:46566271:G:C	N484K	0.998
20:46566271:G:T	N484K	0.998
20:46566274:G:C	S483R	0.998
20:46566274:G:T	S483R	0.998
20:46566276:T:G	S483R	0.998
20:46575592:G:T	A438D	0.998
20:46575604:C:T	G434E	0.998
20:46575605:C:G	G434R	0.998
20:46575605:C:T	G434R	0.998
20:46575626:A:G	W427R	0.998
20:46575626:A:T	W427R	0.998
20:46588081:A:G	W367R	0.998
20:46588081:A:T	W367R	0.998

dbSNP variants (sampled 300 via entrez): RS1000022600 (20:46597053 TA>T,TAA), RS1000033359 (20:46666265 G>A), RS1000047408 (20:46576006 G>A,T), RS1000126072 (20:46631733 C>T), RS1000151699 (20:46591157 A>G), RS1000155466 (20:46631986 T>C), RS1000175972 (20:46672463 C>T), RS1000192934 (20:46599204 C>T), RS1000219852 (20:46642757 G>A,C), RS1000236255 (20:46678398 T>C), RS1000256130 (20:46589581 T>A,C), RS1000262356 (20:46631556 C>A,T), RS1000307380 (20:46684247 T>C), RS1000347998 (20:46673022 G>A), RS1000349448 (20:46587857 C>T)

Disease associations

OMIM: gene MIM:606411 | disease phenotypes: MIM:618384

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate	Strong	Autosomal recessive

Mondo (2): leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate (MONDO:0032716), prostate cancer (MONDO:0008315)

Orphanet (2): Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (Orphanet:615964), Familial prostate cancer (Orphanet:1331)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0002329	Drowsiness
HP:0002344	Progressive neurologic deterioration
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002490	Increased CSF lactate
HP:0002500	Abnormal cerebral white matter morphology
HP:0003621	Juvenile onset
HP:0011463	Childhood onset
HP:0012229	CSF pleocytosis
HP:0012402	Increased urine alpha-ketoglutarate concentration
HP:0033092	Increased urine succinate level
HP:0034649	Elevated urine N-acetylaspartic acid level
HP:6000468	Elevated CSF alpha-ketoglutarate concentration

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001356_3	Gout	1.000000e-07
GCST002313_1	Chronic kidney disease	2.000000e-09
GCST002314_4	Glomerular filtration rate	2.000000e-09
GCST004795_2	Brain volume in infants (white matter)	3.000000e-07
GCST005956_29	Waist-to-hip ratio adjusted for BMI	4.000000e-10
GCST005957_10	Waist-to-hip ratio adjusted for BMI (age <50)	5.000000e-06
GCST005958_17	Waist-to-hip ratio adjusted for BMI (age >50)	3.000000e-06
GCST005962_25	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-09
GCST010396_33	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06
GCST012020_164	Serum metabolite levels	8.000000e-15
GCST012021_89	Serum metabolite levels	8.000000e-15
GCST90026416_2	Mild age-related type 2 diabetes	9.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008370	infant white matter volume measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712947 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2425886	SLC13A3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC13 family of sodium-dependent sulphate/carboxylate transporters

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.80	IC50	160	nM	CHEMBL5405434
5.00	IC50	1e+04	nM	CHEMBL3771118

PubChem BioAssay actives

3 with measured affinity, of 6 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
3-chloro-1-(cyanomethylamino)-7-[1-[6-(difluoromethoxy)-2-methyl-3-pyridinyl]ethyl]-6,8-dihydro-5H-2,7-naphthyridine-4-carbonitrile	1997686: Inhibition of human SLC13A3 in HepG2 cells by measuring citrus uptake	ic50	0.0500	uM
3,3,3-trifluoropropyl N-[3-chloro-5-(trifluoromethyl)phenyl]carbamate	1997686: Inhibition of human SLC13A3 in HepG2 cells by measuring citrus uptake	ic50	0.1600	uM
(2R)-2-hydroxy-2-[2-(2-methoxy-5-methyl-3-pyridinyl)ethyl]butanedioic acid	1280699: Inhibition of NaDC3 (unknown origin) expressed in HEK293 cells assessed as inhibition of [14C]citrate uptake by microbeta plate reader analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	4
sodium arsenite	affects methylation, increases expression	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
bisphenol A	affects expression, increases expression	2
Valproic Acid	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
afuresertib	increases expression	1
propionaldehyde	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	increases expression	1
periodate-oxidized adenosine	affects expression	1
cupric chloride	decreases expression	1
vanadyl sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
Decitabine	affects expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Arsenicals	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Quercetin	affects expression	1
Silicon Dioxide	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Zidovudine	decreases expression, increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 3 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3773094	Binding	Inhibition of NaDC3 (unknown origin) expressed in HEK293 cells assessed as inhibition of [14C]citrate uptake by microbeta plate reader analysis	Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family. — J Med Chem
CHEMBL5209627	Functional	Substrate uptake by the Na(+)/Dicarboxylate Cotransporter 3 (NADC3, SLC13A3) as assessed by the fluorescent FLIPR membrane potential dye in HEK-293 JumpIN-SLC13A3 cells (PubChem AID: 1794820)	Membrane potential based assay for SLC13A3 using HEK-293 SLC13A3 OE cells

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4WQ	SKMEL28-SLC13A3-KO-c3	Cancer cell line	Male
CVCL_D4WR	SKMEL28-SLC13A3-KO-c4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer