SLC19A1

Summary

SLC19A1 (solute carrier family 19 member 1, HGNC:10937) is a protein-coding gene on chromosome 21q22.3, encoding Reduced folate transporter (P41440). Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions. It is a selective cancer dependency (DepMap: 31.4% of cell lines).

The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6573 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 346 total — 13 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 31.4% of screened cell lines
• MANE Select transcript: NM_194255

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10937
Approved symbol	SLC19A1
Name	solute carrier family 19 member 1
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	FOLT, RFC1, IFC-1, RFC, hRFC, RFT-1
Ensembl gene	ENSG00000173638
Ensembl biotype	protein_coding
OMIM	600424
Entrez	6573

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 31 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000311124, ENST00000380010, ENST00000417954, ENST00000427839, ENST00000443742, ENST00000460174, ENST00000461785, ENST00000468508, ENST00000485649, ENST00000486303, ENST00000528477, ENST00000567670, ENST00000650808, ENST00000651099, ENST00000859469, ENST00000859470, ENST00000859471, ENST00000859472, ENST00000859473, ENST00000859474, ENST00000859475, ENST00000859476, ENST00000859477, ENST00000859478, ENST00000859479, ENST00000859480, ENST00000859481, ENST00000930844, ENST00000930845, ENST00000930846, ENST00000930847, ENST00000930848, ENST00000930849, ENST00000930850, ENST00000966362, ENST00000966363

RefSeq mRNA: 6 — MANE Select: NM_194255 NM_001205206, NM_001205207, NM_001352510, NM_001352511, NM_001352512, NM_194255

CCDS: CCDS13725, CCDS56217, CCDS56218

Canonical transcript exons

ENST00000311124 — 6 exons

Exon	Start	End
ENSE00001210607	45530770	45530971
ENSE00001210645	45512565	45516140
ENSE00002299646	45525817	45525958
ENSE00002448210	45531389	45532148
ENSE00002734562	45537771	45538008
ENSE00003841581	45542368	45542440

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 95.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.9903 / max 200.3563, expressed in 1716 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190852	12.7287	1693
190851	1.2749	572
190853	1.0631	615
190860	0.1798	83
190850	0.1397	38
190848	0.1343	60
190861	0.0921	63
190859	0.0817	50
190856	0.0714	27
190846	0.0680	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.77	gold quality
blood	UBERON:0000178	92.84	gold quality
endothelial cell	CL:0000115	90.79	gold quality
choroid plexus epithelium	UBERON:0003911	89.98	gold quality
pigmented layer of retina	UBERON:0001782	89.17	gold quality
retina	UBERON:0000966	89.15	gold quality
duodenum	UBERON:0002114	87.91	gold quality
gall bladder	UBERON:0002110	87.87	gold quality
stromal cell of endometrium	CL:0002255	87.47	gold quality
right lung	UBERON:0002167	87.22	gold quality
putamen	UBERON:0001874	87.01	gold quality
right lobe of liver	UBERON:0001114	86.77	gold quality
mucosa of transverse colon	UBERON:0004991	86.70	gold quality
sural nerve	UBERON:0015488	86.38	gold quality
right frontal lobe	UBERON:0002810	86.14	gold quality
periodontal ligament	UBERON:0008266	85.96	gold quality
placenta	UBERON:0001987	85.89	gold quality
upper lobe of left lung	UBERON:0008952	85.75	gold quality
granulocyte	CL:0000094	85.67	gold quality
caudate nucleus	UBERON:0001873	85.31	gold quality
smooth muscle tissue	UBERON:0001135	85.15	gold quality
endometrium epithelium	UBERON:0004811	85.06	silver quality
upper lobe of lung	UBERON:0008948	84.91	gold quality
right lobe of thyroid gland	UBERON:0001119	84.75	gold quality
monocyte	CL:0000576	84.62	gold quality
spleen	UBERON:0002106	84.54	gold quality
left lobe of thyroid gland	UBERON:0001120	84.36	gold quality
leukocyte	CL:0000738	84.35	gold quality
mononuclear cell	CL:0000842	84.30	gold quality
cingulate cortex	UBERON:0003027	84.27	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	8.00
E-HCAD-35	yes	7.37
E-GEOD-83139	yes	7.30
E-ENAD-27	yes	6.41
E-ANND-3	yes	4.01
E-GEOD-75367	no	41.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CREB1, ETS1, GATA1, GLI1, JUN, MYC, SP1, SP3, TFAP2A, TP53, USF1, USF2, VDR

miRNA regulators (miRDB)

8 targeting SLC19A1, 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-4648	99.91	67.00	710
HSA-MIR-595	98.25	67.44	699
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-299-3P	97.73	66.67	773
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895
HSA-MIR-4654	95.86	65.72	751

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 31.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• A high-abundance C/T696 polymorphism was detected with nearly identical frequencies for both alleles, and a heterozygous C/A1242 sequence variant was identified in two ALL specimens. (PMID:11705857)
• spina bifida risk was influenced by an interaction between a polymorphism of infant RFC1 at nucleotide 80 (A80G) and maternal periconceptional use of vitamins containing folic acid (PMID:11857541)
• transport of RFC1 in epithelial cells (PMID:12087110)
• molecular characterization of human RFC-associated modalities of resistance to various novel antifolates in multiple leukaemia sublines (PMID:12139489)
• suggestion of an intricate regulation of hRFC gene expression involving multiple promoters and non-coding exons, and provision of transcriptional framework for role in pathophysiology of folate deficiency and antifolate drug selectivity (PMID:12144527)
• role of the linker peptide in providing the proper spatial orientation between the two halves of the protein for optimal function, and that this is largely independent of amino acid sequence (PMID:12227830)
• human RFC has a polymorphism that increases promoter activity and may contribute to interpatient variations in hRFC expression and effects on tissue folate homeostasis and antitumor response to antifolates (PMID:12228234)
• relationship of polymorphism G80A in the reduced folate carrier gene to resistance to methotrexate in childhood acute lymphoblastic leukemia (PMID:12411325)
• Role of the E45K-reduced folate carrier gene mutation in methotrexate resistance in human leukemia cells. (PMID:12454742)
• there is a novel mechanism of antifolate resistance that is based on altered expression and function of transcription factors resulting in transcriptional silencing of the hRFC promoter (PMID:12519783)
• Sequence alterations (SSCP) are observed in osteosarcsomas smples. (PMID:12576457)
• RFC-1 A80G variant may contribute to Neural Tube Defect susceptibility in the Italian population. (PMID:12673279)
• Among patient groups with different RFC1 genotypes, red blood cell folate level was not significantly different in ESRD (PMID:12707400)
• results imply that amino acids 40, 44, 48 and, possibly, 42 serve important roles in hRFC transport, albeit not as structural components of the putative transmembrane channel for folate substrates (PMID:12749765)
• RFC1 80G>A is not a major determinant of homoxysteine plasma levels in kidney transplant patients. (PMID:12753319)
• the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in neural tube defect risk (PMID:12855225)
• Transcriptional silencing of the hRFC gene in tumor cell lines resistant to antifolates is a result of loss of function of transcription factors, not promoter methylation. (PMID:14551190)
• Reduced folate carrier protein expression in osteosarcoma. (PMID:14584080)
• Evidence for the 12 transmembrane domains topology model of the reduced folate carrier. (PMID:14602046)
• Aberrant RFC expression may have a role in the already observed deterioration of folate metabolism in Down syndrome. (PMID:15068242)
• co-operative interactions between transcription factors Sp1 and USF are essential for high-level hRFC-B transactivation and imply that these effects are modulated by the family of Ikaros proteins and by histone acetylation (PMID:15214842)
• use of the A1/A2 5’UTR of RFC1 in acute lymphoblastic leukemia may confer a transport phenotype distinct from the other 5’UTRs due to altered translation efficiency and transport properties (PMID:15297414)
• a functional RFC can be reconstituted with RFC half-molecules and localize a critical substrate binding domain to within TMDs 7-12 (PMID:15337749)
• Polymorphisms of reduced folate carrier,aminoimidazole carboxamide ribonucleotide transformylase,and thymidylate synthase genes contribute to the therapeutic response in rheumatoid arthritis patients to methotrexate. (PMID:15457444)
• altered reduced folate carrier sequence changes may have roles in osteosarcoma (PMID:15469899)
• Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation. (PMID:15652157)
• CBS, MTHFR, and SLC19a1 are involved in metabolism of folate and lung cancer risk in China (PMID:15922487)
• G80A reduced folate carrier SNP modulates cellular uptake of folate and affords protection against thrombosis via a non homocysteine related mechanism. (PMID:15964598)
• residues within TMD 11 are likely critical structural and/or functional components of the putative hRFC transmembrane channel for anionic folate and anti-folate substrates (PMID:16115875)
• Significantly higher expression levels of RFC-1 (p = 0.026) and FPGS (p = 0.05) were found in mucosa expressing the splice variant DCC342 compared to mucosa that did not (PMID:16122883)
• our results demonstrate a transcriptionally important region in the hRFC-A1/A2 promoter including E-box and GATA elements, and a transactivation by USF1 and GATA1 proteins (PMID:16225938)
• association between offspring RFC1 GG genotype and the risk of neural tube defects (PMID:16471213)
• The G80A reduced folate carrier SNP had an impact on the absorption and cellular translocation of dietary folate and its association with blood pressure in an elderly population. (PMID:16750224)
• implicate amino acids in transmembrane domains (TMDs) 4, 5, 7, 8, 10, and 11, but not in TMDs 1, 2, 3, 6, 9, or 12, as important structural or functional components of the putative hydrophilic cavity for binding of anionic folate substrates (PMID:16923800)
• results demonstrate an important role for posttranscriptional determinants of cellular hRFC levels and activity. (PMID:17306382)
• Evaluation of RFC-1 gene 80G>A polymorphism may be a useful tool to optimize methotrexate therapy in patients with rheumatoid arthritis. (PMID:17325736)
• This review attempts to provide a comprehensive overview of the biology of the physiologically and pharmacologically important transport system termed the “reduced folate carrier” (RFC). (PMID:17334909)
• For the humanized hRFC mice, levels of B and A1/A2 5’ UTRs predominated in all mice/tissues, thus resembling results in normal human tissues. Lower levels of A and C 5’ UTRs were also detected. (PMID:17983788)
• In DLBCL, genetic and epigenetic alterations of RFC were detected at diagnosis in the absence of a selective MTX pressure, suggesting that these alterations may possibly contribute to the development of lymphoma. (PMID:18028428)
• SLC19A1 and MTHFR genes are differently associated with red cell and plasma folate levels. (PMID:18053808)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc19a1	ENSDARG00000033993
mus_musculus	Slc19a1	ENSMUSG00000001436
rattus_norvegicus	Slc19a1	ENSRNOG00000001232
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), SLC19A3 (ENSG00000135917)

Protein

Protein identifiers

Reduced folate transporter — P41440 (reviewed: P41440)

Alternative names: Cyclic dinucleotide:anion antiporter SLC19A1, Folate:anion antiporter SLC19A1, Intestinal folate carrier 1, Placental folate transporter, Reduced folate carrier protein, Reduced folate transporter 1, Solute carrier family 19 member 1

All UniProt accessions (6): P41440, C9J8K6, C9JKP4, E9PIL5, H0Y4T2, H3BTQ3

UniProt curated annotations — full annotation on UniProt →

Function. Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions. Acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2’-3’-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3’-3’-cGAMP, thus playing a role in triggering larger immune responses. Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates. Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate. Also mediates the import of antifolate drug methotrexate. 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity.

Subcellular location. Cell membrane. Apical cell membrane. Basolateral cell membrane.

Tissue specificity. Placenta, liver, and to a much smaller extent, in lung.

Disease relevance. Megaloblastic anemia, folate-responsive (MEGAF) [MIM:601775] An autosomal recessive metabolic disorder characterized by megaloblastic anemia resulting from decreased folate transport into erythrocytes. Disease manifestations include hemolytic anemia, hyperhomocysteinemia, and low vitamin B12. Serum folate levels are normal, but erythrocyte folate levels are decreased. Treatment with oral folate corrects the anemia and normalizes homocysteine. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 114, folate-responsive (IMD114) [MIM:620603] An autosomal recessive immunologic disorder manifesting in early infancy and characterized by recurrent skin and respiratory infections, mucosal bleeding, oral ulcers, chronic diarrhea, and poor overall growth. Affected individuals have lymphopenia, low serum immunoglobulins, and impaired T cell proliferation. Some patients have global developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Has separate binding pockets for folates and cyclic dinucleotides. Two cyclic dinucleotides can be accommodated in the binding pocket and they are likely transported at the same time.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P41440-1	1	yes
P41440-2	2
P41440-3	3

RefSeq proteins (6): NP_001192135, NP_001192136, NP_001339439, NP_001339440, NP_001339441, NP_919231* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002666	Folate_carrier	Family
IPR028339	SLC19A1	Family
IPR036259	MFS_trans_sf	Homologous_superfamily

Pfam: PF01770

Catalyzed reactions (Rhea), 3 shown:

• 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide(in) + (6S)-5-methyl-5,6,7,8-tetrahydrofolate(out) = 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide(out) + (6S)-5-methyl-5,6,7,8-tetrahydrofolate(in) (RHEA:60460)
• 2’,3’-cGAMP(out) + 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide(in) = 2’,3’-cGAMP(in) + 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide(out) (RHEA:60464)
• 3’,3’-cGAMP(out) + 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide(in) = 3’,3’-cGAMP(in) + 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide(out) (RHEA:60468)

UniProt features (137 total): mutagenesis site 40, binding site 23, helix 21, topological domain 13, transmembrane region 12, strand 7, modified residue 7, sequence variant 4, sequence conflict 3, turn 2, splice variant 2, chain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
7XTK	ELECTRON MICROSCOPY	2.89
9JOZ	ELECTRON MICROSCOPY	2.94
7XQ0	ELECTRON MICROSCOPY	3
8GOE	ELECTRON MICROSCOPY	3
8GOF	ELECTRON MICROSCOPY	3
9JRL	ELECTRON MICROSCOPY	3.25
7TX6	ELECTRON MICROSCOPY	3.3
7XQ2	ELECTRON MICROSCOPY	3.3
9JRM	ELECTRON MICROSCOPY	3.34
7XPZ	ELECTRON MICROSCOPY	3.4
7XQ1	ELECTRON MICROSCOPY	3.4
9JRI	ELECTRON MICROSCOPY	3.43
9JRK	ELECTRON MICROSCOPY	3.44
8HIJ	ELECTRON MICROSCOPY	3.54
8HII	ELECTRON MICROSCOPY	3.57
8DEP	ELECTRON MICROSCOPY	3.6
8HIK	ELECTRON MICROSCOPY	3.72
9JRN	ELECTRON MICROSCOPY	3.74
7TX7	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41440-F1	73.30	0.46

Antibody-complex structures (SAbDab): 3 — 8HII, 8HIJ, 8HIK

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 (23): 48; 49; 123; 133; 133; 134; 137; 149; 157; 164; 281; 282 …

Post-translational modifications (7): 1, 5, 225, 474, 485, 499, 503

Glycosylation sites (1): 58

Mutagenesis-validated functional residues (40):

Position	Phenotype
393	reduces methotrexate uptake. reduces irf3 phosphorylation upon cgamp stimulation.
396	reduces methotrexate uptake. reduces irf3 phosphorylation upon cgamp stimulation.
400	reduces methotrexate uptake. reduces irf3 phosphorylation upon cgamp stimulation.
411	abolishes methotrexate uptake.
42	reduces methotrexate uptake.
42	reduces methotrexate uptake. reduces methotrexate uptake; when associated with k-45.
42	enhances methotrexate uptake.
45	enhances methotrexate uptake.
45	reduces methotrexate uptake. reduces methotrexate uptake; when associated with e-42.
48	reduces methotrexate uptake. reduces methotrexate uptake; when associated with a-126 and a-286.
48	no effect on methotrexate uptake but shifts selectivity towards folinate and pemetrexed.
49	reduces methotrexate uptake. reduces the expression of ifnb1 and cxcl10 upon cgamp stimulation.
58	completely abolishes n-glycosylation without affecting subcellular location or folate:anion antiporter activity.
68	reduces methotrexate uptake.
69	reduces methotrexate uptake.
72	reduces methotrexate uptake.
76	reduces methotrexate uptake.
123	reduces methotrexate uptake.
126	reduces methotrexate uptake. reduces methotrexate uptake; when associated with a-48 and a-286.
130	reduces methotrexate uptake.
133	reduces methotrexate uptake. reduces irf3 phosphorylation upon cgamp stimulation.
133	reduces methotrexate uptake.
149	reduces methotrexate uptake. reduces irf3 phosphorylation upon cgamp stimulation.
150	reduces methotrexate uptake. reduces irf3 phosphorylation upon cgamp stimulation.
157	reduces irf3 phosphorylation upon cgamp stimulation. reduces methotrexate uptake.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines
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: 761 (showing top): GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, E2F_Q4_01, RRAGTTGT_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GRUETZMANN_PANCREATIC_CANCER_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_255, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, MODULE_45, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN

GO Biological Process (16): xenobiotic transmembrane transport (GO:0006855), female pregnancy (GO:0007565), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), obsolete organic anion transport (GO:0015711), folic acid transport (GO:0015884), folic acid metabolic process (GO:0046655), methotrexate transport (GO:0051958), folate transmembrane transport (GO:0098838), cyclic-GMP-AMP transmembrane import across plasma membrane (GO:0140361), positive regulation of cGAS/STING signaling pathway (GO:0141111), transport across blood-brain barrier (GO:0150104), folate import across plasma membrane (GO:1904447), vitamin transmembrane transport (GO:0035461), vitamin transport (GO:0051180), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (11): folic acid binding (GO:0005542), obsolete organic anion transmembrane transporter activity (GO:0008514), folic acid transmembrane transporter activity (GO:0008517), folate:monoatomic anion antiporter activity (GO:0008518), antiporter activity (GO:0015297), methotrexate transmembrane transporter activity (GO:0015350), xenobiotic transmembrane transporter activity (GO:0042910), 2’,3’-cyclic GMP-AMP binding (GO:0061507), cyclic-GMP-AMP transmembrane transporter activity (GO:0140360), protein binding (GO:0005515), vitamin transmembrane transporter activity (GO:0090482)

GO Cellular Component (5): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), brush border membrane (GO:0031526), 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
xenobiotic transport	2
transmembrane transport	2
response to chemical	2
dicarboxylic acid transport	2
vitamin transport	2
folic acid transport	2
vitamin transmembrane transport	2
import across plasma membrane	2
dicarboxylic acid transmembrane transporter activity	2
transmembrane transporter activity	2
plasma membrane region	2
multi-organism reproductive process	1
multi-multicellular organism process	1
modified amino acid transport	1
folic acid-containing compound metabolic process	1
dicarboxylic acid metabolic process	1
nitrogen compound transport	1
carboxylic acid transmembrane transport	1
purine ribonucleotide transport	1
adenine nucleotide transport	1
cyclic nucleotide transport	1
guanine nucleotide transmembrane transport	1
regulation of cytoplasmic pattern recognition receptor signaling pathway	1
positive regulation of pattern recognition receptor signaling pathway	1
cGAS/STING signaling pathway	1
positive regulation of intracellular signal transduction	1
vascular transport	1
folate transmembrane transport	1
transport	1
monoatomic anion transport	1
monoatomic ion transmembrane transport	1
vitamin binding	1
carboxylic acid binding	1
modified amino acid binding	1
heterocyclic compound binding	1
modified amino acid transmembrane transporter activity	1
vitamin transmembrane transporter activity	1
monoatomic anion transmembrane transporter activity	1
folic acid transmembrane transporter activity	1
antiporter activity	1

Protein interactions and networks

STRING

952 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC19A1	GGH	Q92820	931
SLC19A1	TPMT	P51580	924
SLC19A1	MTHFR	P42898	814
SLC19A1	SLC46A1	Q96NT5	806
SLC19A1	MTRR	Q9UBK8	782
SLC19A1	FPGS	Q05932	723
SLC19A1	DHFR	P00374	722
SLC19A1	MTR	Q99707	720
SLC19A1	TYMS	P04818	714
SLC19A1	MTHFD1	P11586	701
SLC19A1	FOLR2	P14207	699
SLC19A1	FOLR1	P15328	689
SLC19A1	ATIC	P31939	661
SLC19A1	TCN2	P20062	652
SLC19A1	SHMT1	P34896	641

IntAct

37 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
CD164L2	SLC19A1	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POTEF	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POM121C	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
VAMP3	SCAMP1	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TNFRSF10C	SLC22A23	psi-mi:“MI:0914”(association)	0.350
NHLRC3	OGG1	psi-mi:“MI:0914”(association)	0.350
SLC19A1	APOB	psi-mi:“MI:0914”(association)	0.350
TNFRSF10C	PLPP3	psi-mi:“MI:0914”(association)	0.350
SLC19A1	TAPBP	psi-mi:“MI:0914”(association)	0.350
SLC19A3	SNAP23	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TMEM216	SNAP23	psi-mi:“MI:2364”(proximity)	0.270
LAMP1	TRAPPC13	psi-mi:“MI:2364”(proximity)	0.270
KRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (172): SLC19A1 (Affinity Capture-MS), SLC19A1 (Proximity Label-MS), SLC19A1 (Proximity Label-MS), SLC19A1 (Affinity Capture-MS), SLC19A1 (Affinity Capture-RNA), SLC19A1 (Proximity Label-MS), SLC19A1 (Proximity Label-MS), SLC19A1 (Proximity Label-MS), SLC19A1 (Proximity Label-MS), SLC19A1 (Proximity Label-MS), SLC19A1 (Proximity Label-MS), SLC19A1 (Affinity Capture-MS), KRT26 (Two-hybrid), SLC19A1 (Affinity Capture-MS), SLC19A1 (Proximity Label-MS)

ESM2 similar proteins: A1A4N1, A8WCG0, B0BNG2, B0S5Y3, B5MEV3, B5X4H8, C1BKZ7, D2HSA6, O54698, O54699, O97704, P41438, P41440, Q06495, Q06496, Q08B29, Q0VC03, Q14542, Q28620, Q29611, Q4FZU9, Q5E9R1, Q5R542, Q5RKL5, Q5XK03, Q60825, Q61124, Q61672, Q62866, Q6GMG6, Q6N075, Q80SU6, Q80WK7, Q863Y7, Q863Y8, Q8BPX9, Q8K0H7, Q8K4R8, Q8N130, Q921Y4

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

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CEBPB	“up-regulates quantity by expression”	SLC19A1	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	SLC19A1	“transcriptional regulation”
SLC19A1	“up-regulates quantity”	(6S)-5-methyltetrahydrofolate(2-)	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NCAM signaling for neurite out-growth	5	37.8×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	4
Uncertain significance	160
Likely benign	110
Benign	29

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1322109	NM_001379500.1(COL18A1):c.3590_3591del (p.Gly1197fs)	Pathogenic
1435551	NM_001379500.1(COL18A1):c.3045del (p.Pro1018fs)	Pathogenic
1446426	NM_001379500.1(COL18A1):c.2776dup (p.Glu926fs)	Pathogenic
1459013	NM_001379500.1(COL18A1):c.3050_3075del (p.Pro1017fs)	Pathogenic
2111410	NM_001379500.1(COL18A1):c.3447_3448delinsAT (p.Arg1150Ter)	Pathogenic
2130137	NM_001379500.1(COL18A1):c.3469del (p.His1157fs)	Pathogenic
2663876	NM_194255.4(SLC19A1):c.1042G>A (p.Gly348Arg)	Pathogenic
280186	NM_001379500.1(COL18A1):c.2979_2980delinsC (p.Pro996fs)	Pathogenic
2868756	NM_001379500.1(COL18A1):c.3307_3325del (p.Tyr1103fs)	Pathogenic
3672060	NM_001379500.1(COL18A1):c.3872del (p.Cys1291fs)	Pathogenic
373961	NM_001379500.1(COL18A1):c.3448C>T (p.Arg1150Ter)	Pathogenic
4715071	NM_001379500.1(COL18A1):c.3743del (p.Gly1248fs)	Pathogenic
548657	NM_001379500.1(COL18A1):c.3959_3960insTGCC (p.Cys1321fs)	Pathogenic
2439255	NM_001379500.1(COL18A1):c.2824_2825del (p.Gly942fs)	Likely pathogenic
3024164	NM_001379500.1(COL18A1):c.3083C>A (p.Ser1028Ter)	Likely pathogenic
3633564	NM_001379500.1(COL18A1):c.2684-1G>A	Likely pathogenic
438063	NM_030582.4(COL18A1):c.3364_3371del (p.Gly1122fs)	Likely pathogenic

SpliceAI

7763 predictions. Top by Δscore:

Variant	Effect	Δscore
21:45493572:CAAGG:C	donor_loss	1.0000
21:45493573:AAGGT:A	donor_loss	1.0000
21:45493574:AGGT:A	donor_loss	1.0000
21:45493577:T:G	donor_loss	1.0000
21:45494538:T:A	acceptor_gain	1.0000
21:45494542:CAG:C	acceptor_loss	1.0000
21:45494543:A:AG	acceptor_gain	1.0000
21:45494543:AG:A	acceptor_gain	1.0000
21:45494544:G:A	acceptor_gain	1.0000
21:45494544:G:GA	acceptor_gain	1.0000
21:45494544:GGGA:G	acceptor_gain	1.0000
21:45494572:G:GG	donor_gain	1.0000
21:45494572:G:T	donor_loss	1.0000
21:45494573:T:A	donor_loss	1.0000
21:45494856:TTGCA:T	acceptor_loss	1.0000
21:45494857:TGCAG:T	acceptor_loss	1.0000
21:45494858:GCAGG:G	acceptor_loss	1.0000
21:45494859:CAGGG:C	acceptor_loss	1.0000
21:45494860:A:AG	acceptor_gain	1.0000
21:45494860:AG:A	acceptor_gain	1.0000
21:45494861:G:GT	acceptor_gain	1.0000
21:45494861:GG:G	acceptor_gain	1.0000
21:45495429:GAGG:G	donor_gain	1.0000
21:45496564:GCAAT:G	donor_gain	1.0000
21:45496567:AT:A	donor_gain	1.0000
21:45496569:G:GG	donor_gain	1.0000
21:45505429:GGG:G	donor_gain	1.0000
21:45505430:GGG:G	donor_gain	1.0000
21:45505962:TCC:T	donor_gain	1.0000
21:45505962:TCCAG:T	donor_loss	1.0000

AlphaMissense

3751 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:45537819:G:C	F47L	0.998
21:45537819:G:T	F47L	0.998
21:45537821:A:G	F47L	0.998
21:45531837:G:C	S167R	0.996
21:45531837:G:T	S167R	0.996
21:45531839:T:G	S167R	0.996
21:45532032:G:C	S102R	0.995
21:45532032:G:T	S102R	0.995
21:45532034:T:G	S102R	0.995
21:45531464:A:G	W292R	0.994
21:45531464:A:T	W292R	0.994
21:45531957:G:C	S127R	0.994
21:45531957:G:T	S127R	0.994
21:45531959:T:G	S127R	0.994
21:45531407:C:G	A311P	0.993
21:45531521:A:G	W273R	0.992
21:45531521:A:T	W273R	0.992
21:45531915:G:C	F141L	0.992
21:45531915:G:T	F141L	0.992
21:45531917:A:G	F141L	0.992
21:45537805:A:G	L52P	0.992
21:45516138:G:C	F432L	0.991
21:45516138:G:T	F432L	0.991
21:45516140:A:G	F432L	0.991
21:45531462:C:A	W292C	0.991
21:45531462:C:G	W292C	0.991
21:45531838:C:A	S167I	0.991
21:45537784:A:G	F59S	0.991
21:45537820:A:C	F47C	0.991
21:45537820:A:G	F47S	0.991

dbSNP variants (sampled 300 via entrez): RS1000011363 (21:45534640 C>A,T), RS1000030357 (21:45550188 C>T), RS1000179804 (21:45508647 G>A), RS1000205807 (21:45511626 G>C), RS1000231072 (21:45503853 G>A), RS1000251796 (21:45551327 T>C), RS1000260835 (21:45503742 T>A,C), RS1000281957 (21:45540446 G>A,T), RS1000346947 (21:45512276 T>C), RS1000426788 (21:45517124 C>T), RS1000431755 (21:45522274 C>A,G), RS1000493062 (21:45514390 G>A), RS1000495869 (21:45555921 CG>C), RS1000500571 (21:45561204 C>G), RS1000521997 (21:45545962 C>T)

Disease associations

OMIM: gene MIM:600424 | disease phenotypes: MIM:267750, MIM:618880, MIM:601775, MIM:211980, MIM:606764, MIM:620603, MIM:116200

GenCC curated gene-disease

Disease	Classification	Inheritance
combined immunodeficiency	Moderate	Autosomal recessive
megaloblastic anemia, folate-responsive	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 114, folate-responsive	Limited	AR

Mondo (11): Knobloch syndrome (MONDO:0800166), Knobloch syndrome 1 (MONDO:0800167), hereditary glaucoma, primary closed-angle (MONDO:0030038), megaloblastic anemia, folate-responsive (MONDO:0011141), lung cancer (MONDO:0008903), gastrointestinal stromal tumor (MONDO:0011719), immunodeficiency 114, folate-responsive (MONDO:0957955), pathologic nystagmus (MONDO:0004843), cataract (MONDO:0005129), inherited retinal dystrophy (MONDO:0019118), combined immunodeficiency (MONDO:0015131)

Orphanet (3): Knobloch syndrome (Orphanet:1571), Gastrointestinal stromal tumor (Orphanet:44890), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000670	Carious teeth
HP:0001047	Atopic dermatitis
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001888	Decreased total lymphocyte count
HP:0001889	Megaloblastic anemia
HP:0001954	Recurrent fever
HP:0001980	Megaloblastic bone marrow
HP:0001981	Schistocytosis
HP:0002028	Chronic diarrhea
HP:0002059	Cerebral atrophy
HP:0002155	Hypertriglyceridemia
HP:0002160	Hyperhomocystinemia
HP:0002188	Delayed CNS myelination
HP:0002240	Hepatomegaly
HP:0002514	Cerebral calcification
HP:0002721	Immunodeficiency
HP:0002783	Recurrent lower respiratory tract infections
HP:0002904	Hyperbilirubinemia
HP:0003212	Increased circulating IgE concentration
HP:0003281	Increased circulating ferritin concentration
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0004315	Decreased circulating IgG concentration
HP:0004802	Episodic hemolytic anemia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004952_39	Ankle injury	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1002021	ankle injury

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
D046152	Gastrointestinal Stromal Tumors	C04.557.450.565.370; C06.301.371.308; C06.405.249.308
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D058499	Retinal Dystrophies	C11.768.585.658
C537209	Knobloch syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4833 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 565,253 (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
CHEMBL1201746	PRALATREXATE	4	14,348
CHEMBL225071	RALTITREXED	4	96,748
CHEMBL225072	PEMETREXED	4	55,761
CHEMBL34259	METHOTREXATE	4	398,396

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

PharmGKB clinical annotations

17 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1051266	Efficacy	2A	methotrexate	Rheumatoid arthritis
rs1051266	Efficacy	3	irinotecan	Colorectal Neoplasms
rs1051266	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma
rs1051266	Toxicity	3	imatinib	Gastrointestinal Stromal Tumors
rs1051266	Toxicity	3	methotrexate	Drug Toxicity;Rheumatoid arthritis
rs1051266	Efficacy	4	methotrexate	Acute lymphoblastic leukemia;Neoplasms
rs1051266	Toxicity	4	methotrexate	Neoplasms
rs1051266	Metabolism/PK	4	methotrexate	Acute lymphoblastic leukemia;Burkitt Lymphoma;Leukemia;Lymphoma;T-Cell;Neoplasms;Osteosarcoma
rs1051296	Metabolism/PK	3	methotrexate	Acute lymphoblastic leukemia
rs1051298	Efficacy	3	pemetrexed	Mesothelioma;Non-Small Cell Lung Carcinoma
rs12659	Efficacy	3	carboplatin;cisplatin;fluorouracil	Uterine Cervical Neoplasm
rs12659	Toxicity	3	imatinib	Gastrointestinal Stromal Tumors
rs2838956	Toxicity	3	methotrexate	adverse events;Rheumatoid arthritis
rs2838958	Efficacy	3	methotrexate	Acute lymphoblastic leukemia
rs3788189	Efficacy	3	pemetrexed	Mesothelioma;Non-Small Cell Lung Carcinoma
rs914232	Efficacy	3	pemetrexed	Mesothelioma;Non-Small Cell Lung Carcinoma
rs9977268	Efficacy	3	methotrexate	Rheumatoid arthritis

PharmGKB variants

17 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7499	COL18A1, SLC19A1		0.00	0
rs12659	SLC19A1	3	1.50	2	carboplatin;cisplatin;fluorouracil;imatinib
rs914232	SLC19A1	3	2.50	1	pemetrexed
rs1051266	SLC19A1	2A	13.38	8	methotrexate;irinotecan;imatinib;Platinum compounds
rs1051296	SLC19A1	3	1.50	1	methotrexate
rs1051298	SLC19A1	3	3.50	1	pemetrexed
rs1131596	SLC19A1		0.00	0
rs2838956	SLC19A1	3	0.00	1	methotrexate
rs3788189	SLC19A1	3	2.00	1	pemetrexed
rs4818789	SLC19A1		0.00	0
rs4819128	SLC19A1		0.00	0
rs7279445	COL18A1, SLC19A1		0.00	0
rs9977268	COL18A1, SLC19A1	3	0.00	1	methotrexate
rs11702425	COL18A1, SLC19A1		0.00	0
rs2838958	SLC19A1	3	2.75	1	methotrexate
rs3788200	SLC19A1		0.00	0
rs17004785	COL18A1, SLC19A1		0.00	0

PharmGKB dosing guidelines

1 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
RNPGx	methotrexate	Annotation of RNPGx Guideline for methotrexate and ABCB1, MTHFR, SLC19A1, SLCO1B1

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC19 family of vitamin transporters

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 9 [PMID: 15615544]	Inhibition	6.55	pKi
methotrexate	Inhibition	5.33	pKi

ChEMBL bioactivities

40 potent at pChembl≥5 of 40 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.16	IC50	0.69	nM	PRALATREXATE
8.20	IC50	6.3	nM	RALTITREXED
7.92	IC50	12	nM	METHOTREXATE
7.70	IC50	20.1	nM	CHEMBL4445651
7.62	IC50	23.8	nM	PEMETREXED
7.58	IC50	26.2	nM	PEMETREXED
7.42	IC50	38.3	nM	CHEMBL3409335
7.27	IC50	54	nM	CHEMBL3628345
7.22	IC50	59.8	nM	CHEMBL3407519
7.21	IC50	62	nM	CHEMBL4538151
7.20	IC50	62.9	nM	CHEMBL3628344
7.18	IC50	66.2	nM	CHEMBL4445651
7.00	IC50	101	nM	CHEMBL1834488
6.97	IC50	106	nM	CHEMBL1834488
6.94	IC50	116	nM	CHEMBL3409334
6.86	IC50	138	nM	PEMETREXED
6.72	IC50	189	nM	CHEMBL3628346
6.71	IC50	197	nM	CHEMBL3628344
6.67	IC50	213	nM	CHEMBL4465095
6.61	IC50	243.2	nM	CHEMBL3409336
6.55	Ki	280	nM	CHEMBL390990
6.52	IC50	304	nM	CHEMBL192632
6.35	IC50	444	nM	CHEMBL1834488
6.33	IC50	468	nM	CHEMBL4557278
6.29	IC50	507	nM	CHEMBL4538151
6.29	IC50	510	nM	CHEMBL4437824
6.28	Ki	530	nM	CHEMBL388501
6.20	IC50	634	nM	CHEMBL4214638
6.19	IC50	642	nM	CHEMBL4471269
6.19	IC50	641	nM	CHEMBL4447805
6.11	IC50	783	nM	CHEMBL4553188
6.09	IC50	808	nM	CHEMBL4444011
5.96	Ki	1100	nM	CHEMBL224946
5.46	Ki	3500	nM	METHOTREXATE

PubChem BioAssay actives

40 with measured affinity, of 136 total; 26 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
Pralatrexate	1380195: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0007	uM
(2S)-2-[[5-[methyl-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methyl]amino]thiophene-2-carbonyl]amino]pentanedioic acid	1164831: Inhibition of RFC (unknown origin) expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0063	uM
Methotrexate	1164831: Inhibition of RFC (unknown origin) expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0120	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	1512992: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0201	uM
Pemetrexed	1512997: Binding affinity to human RFC2 expressed in human HeLa R1-11 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0238	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1197478: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0383	uM
(2S)-2-[[4-[3-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1252411: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0540	uM
(2S)-2-[[5-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]thiophene-2-carbonyl]amino]pentanedioic acid	1197478: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0598	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-2-fluorobenzoyl]amino]pentanedioic acid	1512992: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0620	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1512997: Binding affinity to human RFC2 expressed in human HeLa R1-11 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0629	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1164831: Inhibition of RFC (unknown origin) expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.1010	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1197478: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.1160	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-3-carbonyl]amino]pentanedioic acid	1252411: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.1890	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	1512997: Binding affinity to human RFC2 expressed in human HeLa R1-11 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.2130	uM
(2S)-2-[[5-[5-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)pentyl]thiophene-2-carbonyl]amino]pentanedioic acid	1197478: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.2432	uM
(2S)-2-[6-[(2,4-diaminopteridin-6-yl)methylamino]-3-oxo-1H-isoindol-2-yl]pentanedioic acid	282638: Inhibition of RFC-mediated [3H]MTX influx into human CCRF-CEM cells	ki	0.2800	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]benzoyl]amino]pentanedioic acid	1512992: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.3040	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluoropyridine-2-carbonyl]amino]pentanedioic acid	1512992: Binding affinity to human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.4680	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylamino]benzoyl]amino]pentanedioic acid	1631979: Inhibition of human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.5100	uM
2-[6-[(2,4-diaminopteridin-6-yl)methylamino]-3-oxo-1H-isoindol-2-yl]pentanedioic acid	282638: Inhibition of RFC-mediated [3H]MTX influx into human CCRF-CEM cells	ki	0.5300	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]pyridine-2-carbonyl]amino]pentanedioic acid	1512997: Binding affinity to human RFC2 expressed in human HeLa R1-11 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.6340	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethoxy]benzoyl]amino]pentanedioic acid	1631979: Inhibition of human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.6410	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-formylamino]benzoyl]amino]pentanedioic acid	1631979: Inhibition of human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.6420	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-(2,2,2-trifluoroacetyl)amino]benzoyl]amino]pentanedioic acid	1631979: Inhibition of human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.7830	uM
(2S)-2-[[4-[acetyl-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl]amino]benzoyl]amino]pentanedioic acid	1631979: Inhibition of human RFC expressed in Chinese hamster PC43-10 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.8080	uM
(2S)-2-[6-[(2,4-diaminopteridin-6-yl)methyl-methylamino]-3-oxo-1H-isoindol-2-yl]pentanedioic acid	282638: Inhibition of RFC-mediated [3H]MTX influx into human CCRF-CEM cells	ki	1.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Methotrexate	affects abundance, increases response to substance, decreases reaction, affects expression, decreases activity (+8 more)	15
Folic Acid	affects localization, decreases uptake, decreases expression, affects uptake, increases uptake (+4 more)	10
(+)-JQ1 compound	decreases expression, decreases reaction	4
bisphenol A	decreases expression	2
raltitrexed	decreases reaction, increases transport, decreases response to substance, increases response to substance	2
Pemetrexed	decreases reaction, increases transport, increases response to substance	2
Estradiol	increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	increases methylation, decreases expression	2
Antirheumatic Agents	increases expression, increases response to substance, affects response to substance	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
afuresertib	decreases expression	1
OTX015	decreases expression, decreases reaction	1
ARV-825	affects reaction, decreases expression	1
FR900359	decreases phosphorylation	1
lasiocarpine	increases metabolic processing, decreases expression	1
triphenyl phosphate	affects expression	1
5-methyltetrahydrofolate	decreases uptake, decreases activity	1
methylselenic acid	decreases expression	1
trichostatin A	decreases expression	1
methotrexate polyglutamate	affects abundance	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
potassium chromate(VI)	increases expression	1
coumarin	decreases phosphorylation	1
lometrexol	increases transport, increases response to substance, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, decreases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006403	Binding	Inhibition of human RFC-mediated [3H]MTX transport in Chinese hamster PC43-10 cells at 10 uM	Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity. — J Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3H2	Abcam HEK293T SLC19A1 KO	Transformed cell line	Female
CVCL_D4IH	HCT116-SLC19A1-KO-c4	Cancer cell line	Male
CVCL_D4II	HCT116-SLC19A1-KO-c7	Cancer cell line	Male
CVCL_TL77	HAP1 SLC19A1 (-) 1	Cancer cell line	Male
CVCL_TL78	HAP1 SLC19A1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00158041	PHASE4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960	PHASE4	COMPLETED	Anesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843	PHASE4	TERMINATED	Loading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168	PHASE4	UNKNOWN	Positron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647	PHASE4	COMPLETED	Carotene and Retinol Efficacy Trial
NCT00747773	PHASE4	COMPLETED	Cryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137	PHASE4	COMPLETED	Fentanyl Matrix in Lung Cancer Pain
NCT01381627	PHASE4	UNKNOWN	Safety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506	PHASE4	COMPLETED	Coagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023	PHASE4	COMPLETED	Fractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702	PHASE4	COMPLETED	Randomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318	PHASE4	UNKNOWN	The Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526	PHASE4	COMPLETED	Safety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059	PHASE4	COMPLETED	Ultrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801	PHASE4	UNKNOWN	Efficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789	PHASE4	COMPLETED	An Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221	PHASE4	WITHDRAWN	Regional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544	PHASE4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222	PHASE4	COMPLETED	Effect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645	PHASE4	COMPLETED	Comparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126	PHASE4	UNKNOWN	Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457	PHASE4	TERMINATED	Efficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570	PHASE4	COMPLETED	A Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008	PHASE4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284	PHASE4	UNKNOWN	Rh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913	PHASE4	RECRUITING	Lung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789	PHASE4	RECRUITING	Erector Spinae Block for Thoracic Surgery
NCT05525338	PHASE4	RECRUITING	Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801	PHASE4	RECRUITING	EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933	PHASE4	NOT_YET_RECRUITING	A Study of Camrelizumab Combined With Chemotherapy ± Thalidomide in First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
NCT06646471	PHASE4	RECRUITING	PROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00002550	PHASE3	COMPLETED	Chemotherapy Plus Radiation Therapy With or Without Surgery in Treating Patients With Stage IIIA Non-small Cell Lung Cancer
NCT00002583	PHASE3	COMPLETED	Vinorelbine + Cisplatin or No Further Therapy in Non-small Cell Lung Cancer That Has Been Surgically Removed
NCT00002623	PHASE3	COMPLETED	Chemotherapy Followed by Surgery or Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer