SLC19A3

Summary

SLC19A3 (solute carrier family 19 member 3, HGNC:16266) is a protein-coding gene on chromosome 2q36.3, encoding Thiamine transporter 2 (Q9BZV2). Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism.

This gene encodes a ubiquitously expressed transmembrane thiamine transporter that lacks folate transport activity. Mutations in this gene cause biotin-responsive basal ganglia disease (BBGD); a recessive disorder manifested in childhood that progresses to chronic encephalopathy, dystonia, quadriparesis, and death if untreated. Patients with BBGD have bilateral necrosis in the head of the caudate nucleus and in the putamen. Administration of high doses of biotin in the early progression of the disorder eliminates pathological symptoms while delayed treatment results in residual paraparesis, mild cognitive disability, or dystonia. Administration of thiamine is ineffective in the treatment of this disorder. Experiments have failed to show that this protein can transport biotin. Mutations in this gene also cause a Wernicke’s-like encephalopathy.

Source: NCBI Gene 80704 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 729 total — 52 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 58
• MANE Select transcript: NM_025243

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16266
Approved symbol	SLC19A3
Name	solute carrier family 19 member 3
Location	2q36.3
Locus type	gene with protein product
Status	Approved
Aliases	THTR2, thTr-2, hTHTR2
Ensembl gene	ENSG00000135917
Ensembl biotype	protein_coding
OMIM	606152
Entrez	80704

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 5 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000258403, ENST00000409287, ENST00000409456, ENST00000419059, ENST00000425817, ENST00000431622, ENST00000456524, ENST00000477697, ENST00000642268, ENST00000644224, ENST00000645700, ENST00000645923, ENST00000646591, ENST00000647113, ENST00000676066, ENST00000855517, ENST00000855518, ENST00000855519, ENST00000958931, ENST00000958932, ENST00000958933, ENST00000958934, ENST00000958935, ENST00000958936, ENST00000958937, ENST00000958938

RefSeq mRNA: 5 — MANE Select: NM_025243 NM_001371411, NM_001371412, NM_001371413, NM_001371414, NM_025243

CCDS: CCDS2468

Canonical transcript exons

ENST00000644224 — 6 exons

Exon	Start	End
ENSE00000922430	227698736	227699564
ENSE00000922431	227695889	227696081
ENSE00000922432	227688166	227688307
ENSE00001012555	227717943	227718028
ENSE00003587131	227702169	227702320
ENSE00003823818	227683763	227687573

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 93.35.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0204 / max 331.6539, expressed in 445 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34353	2.7453	441
34352	0.1885	53
34351	0.0867	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
subcutaneous adipose tissue	UBERON:0002190	93.35	gold quality
adipose tissue	UBERON:0001013	93.13	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.22	gold quality
connective tissue	UBERON:0002384	91.00	gold quality
omental fat pad	UBERON:0010414	90.97	gold quality
peritoneum	UBERON:0002358	90.84	gold quality
placenta	UBERON:0001987	90.02	gold quality
right lung	UBERON:0002167	86.82	gold quality
right lobe of liver	UBERON:0001114	86.26	gold quality
jejunal mucosa	UBERON:0000399	85.73	gold quality
gall bladder	UBERON:0002110	84.43	gold quality
duodenum	UBERON:0002114	83.85	gold quality
colonic epithelium	UBERON:0000397	81.56	gold quality
liver	UBERON:0002107	81.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.78	silver quality
buccal mucosa cell	CL:0002336	79.42	gold quality
endothelial cell	CL:0000115	78.69	gold quality
upper lobe of left lung	UBERON:0008952	77.70	gold quality
upper lobe of lung	UBERON:0008948	77.04	gold quality
thoracic mammary gland	UBERON:0005200	76.92	gold quality
mammary gland	UBERON:0001911	76.48	gold quality
sural nerve	UBERON:0015488	75.13	gold quality
mucosa of transverse colon	UBERON:0004991	74.65	gold quality
rectum	UBERON:0001052	73.43	gold quality
pericardium	UBERON:0002407	73.17	gold quality
parietal pleura	UBERON:0002400	73.07	gold quality
left coronary artery	UBERON:0001626	72.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	72.69	gold quality
transverse colon	UBERON:0001157	72.25	gold quality
lung	UBERON:0002048	72.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.53
E-GEOD-111727	no	321.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3

miRNA regulators (miRDB)

119 targeting SLC19A3, 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-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-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-605-3P	99.88	69.22	1833

Literature-anchored findings (GeneRIF, showing 37)

• thiamine transporter THTR2 gene expression is down-regulated in breast cancer (PMID:12861052)
• characterization of the SLC19A3 promoter in vitro and in vivo and demonstrate the importance of an SP1 cis-regulatory element in regulating promoter activity of this important human gene. (PMID:15217784)
• One of the genes up-regulated by SLC19A3 protein (THTR2) transfection was down-regulated by thiamine depletion (CYP4B1) (PMID:15328374)
• Expression of SLC19A3 in leukocytes is a relatively sensitive indicator of marginal biotin deficiency. (PMID:15623830)
• In this segment, each family displayed one of two different missense mutations that altered the coding sequence of SLC19A3, the gene for a transporter related to the reduced-folate (encoded by SLC19A1) and thiamin (encoded by SLC19A2) transporters. (PMID:15871139)
• differentiation of intestinal epithelial cells is associated with an up-regulation in thiamin uptake process which is mediated via transcriptional regulatory mechanisms that involve the SLC19A2 and SLC19A3 genes (PMID:16055442)
• analysis of targeting and trafficking of hTHTR1 and hTHTR2 in epithelial cells (PMID:16371350)
• Thiamine uptake by HEK-293 cells is mediated via a specific pH-dependent process, which involves both the hTHTR-1 and hTHTR-2. (PMID:16705148)
• hTHTR2 mutants (G23V, T422A) both abrogate thiamine transport activity rather than targeting of hTHTR2 to the cell surface. (PMID:16790503)
• THTR2 is involved in thiamine transport by reginal pigment epithelium. (PMID:17463047)
• Pancreatic beta cells and islets take up thiamine by a regulated THTR1/2-mediated process. (PMID:19423748)
• Results suggest that methylation of SLC19A3 promoter could be a novel biomarker for early gastric cancer development. (PMID:19816091)
• The attenuated increase in SLC19A3 expression after HIF-1alpha knockdown suggests a role for HIF-1alpha mediated pathways regulating SLC19A3 gene expression. (PMID:20930543)
• these cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments. (PMID:21176162)
• These results suggested that aberrant SLC19A3 promoter hypermethylation in plasma may be a novel biomarker for breast and gastric cancer diagnosis. (PMID:21789241)
• Two Spanish siblings with a biotin-responsive basal ganglia disease phenotype and mutations in SLC19A3 presented with acute episodes of generalized dystonia (PMID:22777947)
• Glucose-induced decreased expression of thiamine transporters in the tubular epithelium may mediate renal mishandling of thiamine in diabetes. (PMID:23285265)
• Our data shows that SLC19A3 is a new candidate for mutation screening in patients with Leigh syndrome (PMID:23423671)
• A new, severe phenotype of SLC19A3 is identified in early-infantile, lethal encephalopathy characterized by subtotal brain degeneration. (PMID:23482991)
• These studies demonstrate that the human intestinal thiamine uptake is adaptively regulated by the extracellular substrate level via transcriptional regulation of the THTR-2 system, and that SP1 transcriptional factor is involved in this regulation. (PMID:23989004)
• TM4SF4 interacts with hTHTR-2 and influences the physiological function of the thiamine transporter in human intestinal epithelial cells. (PMID:24282057)
• This study provided evidence that biotin-thiamine-responsive basal ganglia disease is the result of SLC19A2 mutation. (PMID:24372704)
• Genetic variation in the SLC19A3 thiamine transporter at 2:228563818T/C may make a modest contribution towards the genetic susceptibility to alcohol dependence syndrome. (PMID:24667528)
• Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. (PMID:26528626)
• Genetic variations in SLC19A3 play an important role in the pathogenesis of severe diabetic retinopathy and nephropathy and may explain why some individuals with type 1 diabetes are less prone than others to develop microvascular complications. (PMID:26718501)
• large genomic deletions occur in the regulatory region of SLC19A3 in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy (PMID:26863430)
• The direct binding and activation of SLC19A3 expression by HIF-1alpha during hypoxic stress (PMID:27743994)
• Genetic screening of SLC19A3 mutation is crucial to diagnosis autosomal recessive biotin-thiamine-responsive basal ganglia disease in asymptomatic relatives presenting with unexplained subacute encephalopathy and abnormal movements. (PMID:27749535)
• The mutation of SLC19A3 is related to Biotin-thiamine-responsive basal ganglia disease. (PMID:27905264)
• Using aggregated exome sequencing data, we calculate the carrier frequency of mutations in SLC19A3 as 1 in 232 individuals in the general population, for an estimated prevalence of the disease of approximately 1 in 215,000 individuals. The disease is thus more frequent than previously recognized (PMID:28402605)
• two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5’ UTR and minimal promoter region. (PMID:28696212)
• Three novel mutations were detected in six patients with Biotin-thiamine responsive basal ganglia disease (PMID:30054086)
• In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free-thiamine in the CSF of SLC19A3 patients. [review] (PMID:31095747)
• Obesity status modifies the association between rs7556897T>C in the intergenic region SLC19A3-CCL20 and blood pressure in French children. (PMID:32238601)
• pH-dependent pyridoxine transport by SLC19A2 and SLC19A3: Implications for absorption in acidic microclimates. (PMID:33008889)
• Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment. (PMID:34614013)
• Structural basis of thiamine transport and drug recognition by SLC19A3. (PMID:39358356)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc19a3a	ENSDARG00000006447
mus_musculus	Slc19a3	ENSMUSG00000038496
rattus_norvegicus	Slc19a3	ENSRNOG00000057256
drosophila_melanogaster	CG17036	FBGN0032449
drosophila_melanogaster	CG14694	FBGN0037845
drosophila_melanogaster	CG6574	FBGN0037846
caenorhabditis_elegans		WBGENE00007388
caenorhabditis_elegans		WBGENE00018138
caenorhabditis_elegans		WBGENE00044738

Paralogs (2): SLC19A2 (ENSG00000117479), SLC19A1 (ENSG00000173638)

Protein

Protein identifiers

Thiamine transporter 2 — Q9BZV2 (reviewed: Q9BZV2)

Alternative names: Solute carrier family 19 member 3

All UniProt accessions (10): A0A2R8Y655, A0A2R8Y694, A0A2R8YFC5, A0A2R8YHG5, B8ZZ39, B8ZZW1, C9IZI1, C9J4J5, Q9BZV2, E7EM61

UniProt curated annotations — full annotation on UniProt →

Function. Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism. Has no folate transport activity. Mediates H(+)-dependent pyridoxine transport.

Subcellular location. Membrane.

Tissue specificity. Widely expressed but most abundant in placenta, kidney and liver.

Disease relevance. Basal ganglia disease, biotin-thiamine responsive (BTBGD) [MIM:607483] An autosomal recessive metabolic disorder characterized by episodic encephalopathy, often triggered by febrile illness, presenting as confusion, seizures, external ophthalmoplegia, dysphagia, and sometimes coma and death. If untreated, encephalopathies can result in permanent dystonia. Brain imaging may show characteristic bilateral lesions of the basal ganglia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Pyridoxine transport is inhibited by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and carbonyl cyanide m-chlorophenylhydrazone (CCCP).

Similarity. Belongs to the reduced folate carrier (RFC) transporter (TC 2.A.48) family.

RefSeq proteins (5): NP_001358340, NP_001358341, NP_001358342, NP_001358343, NP_079519* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002666	Folate_carrier	Family
IPR028337	ThTr-2	Family
IPR036259	MFS_trans_sf	Homologous_superfamily

Pfam: PF01770

Catalyzed reactions (Rhea), 2 shown:

• thiamine(out) + H(+)(in) = thiamine(in) + H(+)(out) (RHEA:71271)
• pyridoxine(out) + n H(+)(out) = pyridoxine(in) + n H(+)(in) (RHEA:76203)

UniProt features (74 total): helix 20, topological domain 13, transmembrane region 12, site 7, mutagenesis site 7, turn 5, sequence variant 4, glycosylation site 2, strand 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
9G5K	ELECTRON MICROSCOPY	2.87
8S5Z	ELECTRON MICROSCOPY	3
8Z7Y	ELECTRON MICROSCOPY	3.02
8S5W	ELECTRON MICROSCOPY	3.05
8Z7S	ELECTRON MICROSCOPY	3.05
8S4U	ELECTRON MICROSCOPY	3.09
8Z7W	ELECTRON MICROSCOPY	3.09
8Z7U	ELECTRON MICROSCOPY	3.1
8Z7V	ELECTRON MICROSCOPY	3.1
8Z7R	ELECTRON MICROSCOPY	3.15
8S5U	ELECTRON MICROSCOPY	3.28
9HJD	ELECTRON MICROSCOPY	3.35
8Z7X	ELECTRON MICROSCOPY	3.36
8Z7T	ELECTRON MICROSCOPY	3.39
8S61	ELECTRON MICROSCOPY	3.53
8XV2	ELECTRON MICROSCOPY	3.7
8XV5	ELECTRON MICROSCOPY	3.7
8S62	ELECTRON MICROSCOPY	3.75
8XV9	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZV2-F1	81.96	0.55

Antibody-complex structures (SAbDab): 5 — 8S4U, 8S5U, 8S5W, 8S61, 9G5K

Functional residue map

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

Catalytic / active sites (7): 86 (essential for pyridoxine transport); 87 (essential for pyridoxine transport); 91 (essential for pyridoxine transport); 93 (essential for pyridoxine transport); 94 (essential for pyridoxine transport); 168 (essential for pyridoxine transport); 173 (essential for pyridoxine transport)

Glycosylation sites (2): 45, 166

Mutagenesis-validated functional residues (7):

Position	Phenotype
86	significant decrease in pyridoxine transport.
87	significant decrease in pyridoxine transport.
91	significant decrease in pyridoxine transport.
93	significant decrease in pyridoxine transport.
94	significant decrease in pyridoxine transport.
168	significant decrease in pyridoxine transport.
173	significant decrease in pyridoxine transport.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196819	Vitamin B1 (thiamin) metabolism
R-HSA-1430728	Metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors

MSigDB gene sets: 172 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_VITAMIN_BIOSYNTHETIC_PROCESS, GOBP_SULFUR_COMPOUND_TRANSPORT, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_VITAMIN_TRANSPORT, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_TRANSMEMBRANE_TRANSPORT, GOBP_ORGANIC_CATION_TRANSPORT, OCT1_B

GO Biological Process (8): thiamine diphosphate biosynthetic process (GO:0009229), thiamine transport (GO:0015888), pyridoxine transport (GO:0031923), thiamine-containing compound metabolic process (GO:0042723), thiamine transmembrane transport (GO:0071934), vitamin transmembrane transport (GO:0035461), vitamin transport (GO:0051180), transmembrane transport (GO:0055085)

GO Molecular Function (3): thiamine transmembrane transporter activity (GO:0015234), protein binding (GO:0005515), vitamin transmembrane transporter activity (GO:0090482)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vitamin transport	2
vitamin transmembrane transport	2
transport	2
thiamine diphosphate metabolic process	1
thiamine-containing compound biosynthetic process	1
organophosphate biosynthetic process	1
nitrogen compound transport	1
sulfur compound transport	1
organic hydroxy compound transport	1
vitamin B6 transport	1
sulfur compound metabolic process	1
pyrimidine-containing compound metabolic process	1
thiamine transport	1
azole transmembrane transport	1
pyrimidine-containing compound transmembrane transport	1
transmembrane transport	1
cellular process	1
thiamine transmembrane transport	1
vitamin transmembrane transporter activity	1
azole transmembrane transporter activity	1
sulfur compound transmembrane transporter activity	1
binding	1
transmembrane transporter activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC19A3	TPK1	Q9H3S4	780
SLC19A3	SLC25A19	Q9HC21	747
SLC19A3	BTD	P43251	726
SLC19A3	LIPT1	Q9Y234	519
SLC19A3	SLC29A4	Q7RTT9	512
SLC19A3	TKTL1	P51854	500
SLC19A3	LIPT2	A6NK58	496
SLC19A3	TKT	P29401	490
SLC19A3	SLC46A1	Q96NT5	485
SLC19A3	TKTL2	Q9H0I9	477
SLC19A3	PDHX	O00330	452
SLC19A3	SLC47A2	Q86VL8	450
SLC19A3	SURF1	Q15526	447
SLC19A3	LIAS	O43766	439
SLC19A3	SLC5A6	Q9Y289	438

IntAct

44 interactions, top by confidence:

A	B	Type	Score
SLC19A3	GET1	psi-mi:“MI:0915”(physical association)	0.560
SLC19A3	TMEM242	psi-mi:“MI:0915”(physical association)	0.560
ZFPL1	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
GET1	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
LAT	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
PLPPR2	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
SLC19A3	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
THBD	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
ARLN	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
CYP4F2	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
CYB561	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
SLC19A3	TMEM14A	psi-mi:“MI:0915”(physical association)	0.560
SLC19A3	TAB2	psi-mi:“MI:0915”(physical association)	0.370
SLC19A3	CREB3L4	psi-mi:“MI:0915”(physical association)	0.370
C3orf38	SLC19A3	psi-mi:“MI:0915”(physical association)	0.370
SLC19A3	CREB3	psi-mi:“MI:0915”(physical association)	0.370
PDZK1P1	ZBTB5	psi-mi:“MI:0914”(association)	0.350
PDZK1	ZBTB5	psi-mi:“MI:0914”(association)	0.350
SLC19A3	SNAP23	psi-mi:“MI:0914”(association)	0.350
LAT	SLC19A3	psi-mi:“MI:0915”(physical association)	0.000
PLPPR2	SLC19A3	psi-mi:“MI:0915”(physical association)	0.000
SLC19A3	TMEM14B	psi-mi:“MI:0915”(physical association)	0.000
	SLC19A3	psi-mi:“MI:0915”(physical association)	0.000
THBD	SLC19A3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (99): SLC19A3 (Two-hybrid), SLC19A3 (Affinity Capture-MS), SLC19A3 (Two-hybrid), SLC19A3 (Two-hybrid), SLC19A3 (Two-hybrid), TMEM14B (Two-hybrid), ZFPL1 (Two-hybrid), C4orf3 (Two-hybrid), THBD (Two-hybrid), CYP4F2 (Two-hybrid), LAT (Two-hybrid), TMEM242 (Two-hybrid), FXYD6-FXYD2 (Two-hybrid), SLC19A3 (Affinity Capture-MS), SLC19A3 (Proximity Label-MS)

ESM2 similar proteins: A2AVZ9, A4IHK6, A4QN56, A5D7V7, B0S5Y3, B2RXV4, B5X4H8, O00400, O60779, O75387, P41438, P58355, P60815, Q04991, Q0VC03, Q0VCM6, Q1JPD8, Q28FF3, Q4LE88, Q4R877, Q569T7, Q5BK75, Q5E9R1, Q5R542, Q5RBM3, Q5RF58, Q62866, Q6AYY8, Q6GMG6, Q6N075, Q6PB15, Q71B07, Q8BSM7, Q8CGA3, Q8N370, Q8NBI5, Q91X85, Q921Y4, Q944P0, Q99J27

Diamond homologs: O45166, O60779, P41438, P41440, Q17766, Q22931, Q4R877, Q62866, Q99PL8, Q9BZV2, Q9EQN9, P42557, Q53S99, Q559K0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SP3	“up-regulates quantity by expression”	SLC19A3	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	SLC19A3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	21
Uncertain significance	288
Likely benign	234
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071924	NM_025243.4(SLC19A3):c.776_777del (p.Val259fs)	Pathogenic
1073682	NM_025243.4(SLC19A3):c.1257del (p.Ile420fs)	Pathogenic
1074726	NM_025243.4(SLC19A3):c.1164del (p.Thr388_Ile389insTer)	Pathogenic
1216993	NM_025243.4(SLC19A3):c.171del (p.Val58fs)	Pathogenic
1332819	NM_025243.4(SLC19A3):c.307dup (p.Val103fs)	Pathogenic
1453971	NM_025243.4(SLC19A3):c.855G>A (p.Trp285Ter)	Pathogenic
1459929	NM_025243.4(SLC19A3):c.426del (p.Cys143fs)	Pathogenic
1460288	NC_000002.11:g.(?228552113)(228567034_?)del	Pathogenic
1505253	NM_025243.4(SLC19A3):c.1172+2T>G	Pathogenic
1526958	GRCh37/hg19 2q36.3(chr2:228534400-228589902)x1	Pathogenic
162137	NM_025243.4(SLC19A3):c.20C>A (p.Ser7Ter)	Pathogenic
190224	NM_025243.4(SLC19A3):c.74dup (p.Ser26fs)	Pathogenic
2022485	NM_025243.4(SLC19A3):c.160G>T (p.Glu54Ter)	Pathogenic
215158	NM_025243.4(SLC19A3):c.1332C>G (p.Ser444Arg)	Pathogenic
2697815	NM_025243.4(SLC19A3):c.885_888dup (p.Asn297fs)	Pathogenic
2700091	NM_025243.4(SLC19A3):c.795G>A (p.Trp265Ter)	Pathogenic
2734426	NM_025243.4(SLC19A3):c.507C>G (p.Tyr169Ter)	Pathogenic
2759263	NM_025243.4(SLC19A3):c.12C>G (p.Tyr4Ter)	Pathogenic
2762268	NM_025243.4(SLC19A3):c.125dup (p.Asp43fs)	Pathogenic
2780017	NM_025243.4(SLC19A3):c.816C>A (p.Cys272Ter)	Pathogenic
2824259	NM_025243.4(SLC19A3):c.129dup (p.Lys44Ter)	Pathogenic
2832768	NM_025243.4(SLC19A3):c.856del (p.Ala286fs)	Pathogenic
2836128	NM_025243.4(SLC19A3):c.1212dup (p.Val406fs)	Pathogenic
2840050	NM_025243.4(SLC19A3):c.177G>A (p.Trp59Ter)	Pathogenic
2840270	NM_025243.4(SLC19A3):c.475C>T (p.Gln159Ter)	Pathogenic
2859471	NM_025243.4(SLC19A3):c.701del (p.Thr234fs)	Pathogenic
2917962	NM_025243.4(SLC19A3):c.597del (p.His200fs)	Pathogenic
3069169	NM_025243.4(SLC19A3):c.696del (p.Lys232fs)	Pathogenic
3247243	NC_000002.11:g.(?228566865)(228567034_?)del	Pathogenic
3247244	NC_000002.11:g.(?228552862)(228553043_?)del	Pathogenic

SpliceAI

1052 predictions. Top by Δscore:

Variant	Effect	Δscore
2:227688161:CTTA:C	donor_loss	1.0000
2:227688163:TACC:T	donor_loss	1.0000
2:227688165:CC:C	donor_loss	1.0000
2:227702326:C:CT	acceptor_gain	1.0000
2:227687572:AA:A	acceptor_gain	0.9900
2:227687574:C:CC	acceptor_gain	0.9900
2:227695887:A:AC	donor_gain	0.9900
2:227695888:C:CC	donor_gain	0.9900
2:227695888:CA:C	donor_gain	0.9900
2:227695888:CACTG:C	donor_gain	0.9900
2:227696010:C:CT	donor_gain	0.9900
2:227699666:T:TC	acceptor_gain	0.9900
2:227702327:A:T	acceptor_gain	0.9900
2:227717938:CTTA:C	donor_loss	0.9900
2:227717939:TTACC:T	donor_loss	0.9900
2:227717941:ACCT:A	donor_loss	0.9900
2:227717942:C:CG	donor_loss	0.9900
2:227717942:CCTA:C	donor_gain	0.9900
2:227688305:AATC:A	acceptor_loss	0.9800
2:227688306:AT:A	acceptor_gain	0.9800
2:227688308:C:CC	acceptor_gain	0.9800
2:227696011:C:CT	donor_gain	0.9800
2:227698730:GCTTA:G	donor_loss	0.9800
2:227698731:CTTAC:C	donor_loss	0.9800
2:227698732:TTA:T	donor_loss	0.9800
2:227698733:TA:T	donor_loss	0.9800
2:227702321:C:CC	acceptor_gain	0.9800
2:227702329:A:AC	acceptor_gain	0.9800
2:227702329:A:C	acceptor_gain	0.9800
2:227688303:GAAAT:G	acceptor_gain	0.9700

AlphaMissense

3239 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:227699295:G:C	S140R	0.990
2:227699295:G:T	S140R	0.990
2:227699297:T:G	S140R	0.990
2:227702217:G:C	F34L	0.983
2:227702217:G:T	F34L	0.983
2:227702219:A:G	F34L	0.983
2:227698808:A:G	W303R	0.982
2:227698808:A:T	W303R	0.982
2:227699280:G:C	S145R	0.982
2:227699280:G:T	S145R	0.982
2:227699282:T:G	S145R	0.982
2:227699350:G:T	A122D	0.981
2:227702261:A:G	C20R	0.980
2:227699362:G:T	A118D	0.979
2:227699375:C:A	G114W	0.978
2:227699448:A:C	S89R	0.978
2:227699448:A:T	S89R	0.978
2:227699450:T:G	S89R	0.978
2:227702251:C:T	G23D	0.978
2:227698865:A:G	W284R	0.977
2:227698865:A:T	W284R	0.977
2:227688259:A:C	F407L	0.972
2:227688259:A:T	F407L	0.972
2:227688261:A:G	F407L	0.972
2:227698806:C:A	W303C	0.972
2:227698806:C:G	W303C	0.972
2:227702252:C:G	G23R	0.972
2:227699272:A:G	L148P	0.971
2:227699374:C:T	G114E	0.971
2:227699266:G:T	A150D	0.969

dbSNP variants (sampled 300 via entrez): RS1000108682 (2:227685064 G>A), RS1000182811 (2:227692888 A>T), RS1000236352 (2:227702777 T>A), RS1000318754 (2:227713548 C>CTGG), RS1000406747 (2:227711047 C>T), RS1000567548 (2:227702475 C>A,T), RS1000582535 (2:227689451 A>G), RS1000669067 (2:227700676 G>C), RS1000676185 (2:227698080 A>G), RS1000707312 (2:227698286 A>G), RS1000710664 (2:227695244 T>C), RS1000759821 (2:227711258 A>T), RS1000788130 (2:227691273 T>C), RS1000845931 (2:227689912 T>C), RS1000869723 (2:227716188 A>G,T)

Disease associations

OMIM: gene MIM:606152 | disease phenotypes: MIM:607483

GenCC curated gene-disease

Disease	Classification	Inheritance
Leigh syndrome	Definitive	Autosomal recessive
biotin-responsive basal ganglia disease	Definitive	Autosomal recessive
thiamine-responsive encephalopathy	Supportive	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
infantile spams-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR

Mondo (6): biotin-responsive basal ganglia disease (MONDO:0011841), intellectual disability (MONDO:0001071), Leigh syndrome (MONDO:0009723), (MONDO:0016050), (MONDO:0016815), infantile spams-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome (MONDO:0016981)

Orphanet (3): Thiamine-responsive encephalopathy (Orphanet:199348), Biotin-thiamine-responsive basal ganglia disease (Orphanet:65284), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000639	Nystagmus
HP:0000711	Restlessness
HP:0000737	Irritability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001289	Confusion
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001945	Fever
HP:0002013	Vomiting
HP:0002015	Dysphagia
HP:0002062	Abnormal pyramidal tract morphology
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002072	Chorea
HP:0002093	Respiratory insufficiency
HP:0002133	Status epilepticus
HP:0002134	Abnormal basal ganglia morphology
HP:0002179	Opisthotonus
HP:0002273	Tetraparesis

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001762_149	Obesity-related traits	8.000000e-06
GCST007797_38	Asthma onset (childhood vs adult)	7.000000e-11
GCST007798_51	Asthma	3.000000e-07
GCST007800_4	Asthma (childhood onset)	2.000000e-19
GCST009798_81	Asthma	1.000000e-09
GCST010984_8	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	5.000000e-13
GCST010985_7	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	5.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C537658	Basal ganglia disease, biotin-responsive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC19 family of vitamin transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
bisphenol A	decreases methylation, increases expression, affects cotreatment	2
sodium arsenite	affects methylation, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases methylation, decreases expression	2
Thiamine	increases expression, decreases reaction, increases uptake	2
Cyclosporine	decreases expression	2
FR900359	decreases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
pirinixic acid	increases expression, affects binding, increases activity	1
trichostatin A	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	decreases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression	1
Ethanol	decreases expression	1
Amprolium	increases uptake, decreases reaction	1
Cadmium	decreases expression	1
Chloroquine	decreases reaction, increases uptake	1
Cisplatin	decreases expression	1

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D4S4	HuH7-SLC19A3-KO-c2	Cancer cell line	Male
CVCL_D4S5	HuH7-SLC19A3-KO-c6	Cancer cell line	Male
CVCL_E4C4	KAIMRCi004-A	Induced pluripotent stem cell	Female
CVCL_E4C5	KAIMRCi004-B	Induced pluripotent stem cell	Female
CVCL_TL81	HAP1 SLC19A3 (-) 1	Cancer cell line	Male
CVCL_XS91	HAP1 SLC19A3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication