SLC46A1

Summary

SLC46A1 (solute carrier family 46 member 1, HGNC:30521) is a protein-coding gene on chromosome 17q11.2, encoding Proton-coupled folate transporter (Q96NT5). Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force.

This gene encodes a transmembrane proton-coupled folate transporter protein that facilitates the movement of folate and antifolate substrates across cell membranes, optimally in acidic pH environments. This protein is also expressed in the brain and choroid plexus where it transports folates into the central nervous system. This protein further functions as a heme transporter in duodenal enterocytes, and potentially in other tissues like liver and kidney. Its localization to the apical membrane or cytoplasm of intestinal cells is modulated by dietary iron levels. Mutations in this gene are associated with autosomal recessive hereditary folate malabsorption disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 113235 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary folate malabsorption (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 228 total — 14 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_080669

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30521
Approved symbol	SLC46A1
Name	solute carrier family 46 member 1
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	HCP1, MGC9564, PCFT, HsPCFT, hPCFT
Ensembl gene	ENSG00000076351
Ensembl biotype	protein_coding
OMIM	611672
Entrez	113235

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000578217, ENST00000581516, ENST00000582590, ENST00000582735, ENST00000584426, ENST00000584995, ENST00000612814, ENST00000618626, ENST00000619923, ENST00000884019, ENST00000942091

RefSeq mRNA: 2 — MANE Select: NM_080669 NM_001242366, NM_080669

CCDS: CCDS74019, CCDS74020

Canonical transcript exons

ENST00000612814 — 5 exons

Exon	Start	End
ENSE00003712470	28404616	28405468
ENSE00003714955	28402238	28402321
ENSE00003719217	28400610	28400766
ENSE00003736461	28405887	28406212
ENSE00003736542	28394642	28399713

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 97.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2197 / max 278.6604, expressed in 1541 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165013	8.1606	1541
165014	0.0527	26
165012	0.0064	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	97.44	gold quality
duodenum	UBERON:0002114	95.51	gold quality
oviduct epithelium	UBERON:0004804	94.50	gold quality
right adrenal gland	UBERON:0001233	91.63	gold quality
right adrenal gland cortex	UBERON:0035827	90.86	gold quality
left adrenal gland cortex	UBERON:0035825	90.78	gold quality
left adrenal gland	UBERON:0001234	90.77	gold quality
right lobe of liver	UBERON:0001114	90.24	gold quality
right uterine tube	UBERON:0001302	90.08	gold quality
adrenal cortex	UBERON:0001235	89.63	gold quality
adrenal gland	UBERON:0002369	89.30	gold quality
body of pancreas	UBERON:0001150	88.76	gold quality
adenohypophysis	UBERON:0002196	88.15	gold quality
islet of Langerhans	UBERON:0000006	88.11	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.00	gold quality
pancreas	UBERON:0001264	87.69	gold quality
cerebellar hemisphere	UBERON:0002245	87.69	gold quality
cerebellar cortex	UBERON:0002129	87.57	gold quality
endothelial cell	CL:0000115	87.48	silver quality
pituitary gland	UBERON:0000007	87.33	gold quality
liver	UBERON:0002107	86.89	gold quality
cerebellum	UBERON:0002037	86.69	gold quality
fallopian tube	UBERON:0003889	86.07	gold quality
spleen	UBERON:0002106	85.48	gold quality
ventricular zone	UBERON:0003053	85.31	gold quality
ganglionic eminence	UBERON:0004023	84.60	gold quality
cortical plate	UBERON:0005343	84.21	gold quality
right coronary artery	UBERON:0001625	84.07	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.96	gold quality
nucleus accumbens	UBERON:0001882	83.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDX2, CEBPA, HNF4A, JUN, KLF4, NRF1, VDR, YY1

miRNA regulators (miRDB)

168 targeting SLC46A1, 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-5692A	100.00	74.40	6850
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836

Literature-anchored findings (GeneRIF, showing 40)

• A loss-of-function mutation in PCFT/HCP1 is the molecular basis for hereditary folate malabsorption in a family with this disease. (PMID:17129779)
• HCP1 expression in different cells implies a functional role in tissues other than the duodenum (PMID:17156779)
• Our data revealed low-level wider expression of human HCP1 transcript in multiple tissues suggesting that it is responsible for heme transport in the body, not the intestine alone. (PMID:17335806)
• Mutations in the PCFT gene is associated with malabsorption syndromes (PMID:17446347)
• Data suggest that hPCFT/HCP1 is responsible for the intestinal absorption of folate and also methotrexate. (PMID:17475902)
• HCP-1 expression in human macrophages is downregulated by TLR agonists & IFN-gamma, upregulated by dexamethasone. In early endosomes, it colocalizes with endocytosed Hb-haptoglobin (Hp) complexes, taken up by the CD163 scavenger receptor pathway. (PMID:17947394)
• Present information regarding structure-function and membrane targeting of the hPCFT polypeptide, as well as the mechanisms that control its steady-state expression in polarized cells. (PMID:18003745)
• Intestinal folate uptake process undergoes differentiation-dependent regulation and that this regulation is mediated via changes in the level of expression of both the RFC and PCFT. (PMID:18650265)
• HFM was shown to be due to loss-of-function mutations in a proton-coupled folate transporter (PCFT),[3] and [4] allowing the possibility of rapid diagnosis and correlations among specific mutations, clinical manifestations, and outcome. (PMID:18718264)
• These findings constitute the first demonstration of the dominant epigenetic silencing of the PCFT gene in leukemia cells. (PMID:18817749)
• that PCFT plays a role in FRalpha-mediated endocytosis by serving as a route of export of folates from acidified endosomes (PMID:19074442)
• The entire HCP1 coding region was examined in 788 participants from the HEIRS study. 8 different heterozygous variants were found; 5 non-synonymous coding-region variants displayed high transferrin saturations. (PMID:19176287)
• Observations suggest that the E185 residue plays an important role in the coupled flows of protons and folate mediated by SLC46A1. (PMID:19403800)
• These findings constitute the first demonstration that a basic amino acid at position 113 is required for folate substrate binding by SLC46A1. (PMID:19508863)
• This is the first functional identification of the minimal PCFT promoter harboring crucial GC-box elements that markedly contribute to its transcriptional activation via putative interaction with distal YY1 and AP1 enhancer elements. (PMID:19643086)
• hPCFT transporter activity can be modulated by many drugs in clinical use, and expression of this transporter in the gastrointestinal tract is higher in the duodenum than more distal sites (duodenum > ileum > colon) (PMID:19762432)
• Direct sequencing of PCFT revealed a novel homozygous frameshift mutation (c.194dupG) at a mononucleotide repeat in exon 1 predicted to result in a truncated protein (p.Cys66LeufsX99) causing hereditary folate malabsorptionl (PMID:20005757)
• Using immunohistochemistry, PCFT was localized to microvillous plasma membrane of syncytiotrophoblasts during first trimester and at term. (PMID:20036773)
• analyses establish a PCFT secondary structure of 12 transmembrane domains with the N- and C- termini directed to the cytoplasm (PMID:20225891)
• Data suggest that mutation of the R376 residue of SLC46A1 to Gln impairs proton binding which modulates the folate-binding pocket and depresses the rate of conformational alteration of the carrier. (PMID:20686069)
• the obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1 (PMID:20724482)
• The report on a Turkish family with 2 children with HFM who have a novel homozygous frameshift mutation (c.204 205delCC) in the PCFT gene. (PMID:20795774)
• D156 plays a critical role in PCFT protein stability, and D109, located in the first intracellular loop between the second and third transmembrane domains, is absolutely required for PCFT function. (PMID:20805364)
• Data show that the loss of activity of mutant PCFTs was shown to be due to impaired protein stability and expression. (PMID:21256110)
• novel mutations are described in three subjects with folate malabsorption: A335D/N68Kfs (c.1004C>A/c.204-205delCC), compound heterozygous mutations, and two homozygous PCFT mutations, G338R (c.1012G>C) and E9Gfs (c.17-18insC). (PMID:21333572)
• PCFT 928GG genotype had significantly higher plasma Hcy concentrations compared with carriers of the A allele. (PMID:21338559)
• These findings are consistent with a common mutation in the PCFT gene causing hereditary folate malabsorption that has disseminated to Puerto Ricans who have migrated to mainland United States (PMID:21489556)
• Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function. (PMID:21602279)
• Identification and functional impact of homo-oligomers of the human proton-coupled folate transporter. (PMID:22179615)
• the P425R-PCFT mutation produces a conformational change that fully preserves pemetrexed binding but markedly impairs binding of methotrexate and other folates to the carrier. (PMID:22345511)
• HCP1 is involved in low-affinity heme-Fe uptake by Caco-2 cells. (PMID:22496243)
• The role of GXXG motif is consistent with a molecular structural model in which this motif and Ile188 are accessible to the PCFT aqueous translocation pathway. (PMID:22785121)
• Loss of intrinsic Gly338Cys-PCFT function is due solely to impaired oscillation of the carrier between its conformational states. (PMID:22843796)
• PCFT is abundantly expressed in human tumors and is active at pHs characterizing the tumor microenvironment (PMID:22954694)
• These results suggest that the activity of PCFT promoter is basically induced by KLF4 and the gradiented expression profile of PCFT may be at least in part accounted for by those of HNF4alpha, CDX2 and C/EBPalpha. (PMID:23313509)
• Two loss-of-function mutations in the fourth transmembrane domain of proton-coupled folate transporter (PCFT) play a role in hereditary folate malabsorption in subjects with this disorder. (PMID:23552283)
• The monomeric state of proton-coupled folate transporter is the functional state, substrate translocation does not depend on homo-oligomerization. (PMID:23601781)
• At weakly acidic pH (6.5), bisulfite and nitrite exhibited much stronger inhibition of PCFT-mediated transport. (PMID:23609145)
• SLC46A1 SNP had a statistically significant association with HDL plasma levels. (PMID:23656756)
• The molecular bases for methotrexate resistance associated with loss of SLC19A1 transport and for hereditary folate malabsorption, attributable to mutant SLC46A1, were determned (review). (PMID:24396145)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc46a1	ENSDARG00000026149
mus_musculus	Slc46a1	ENSMUSG00000020829
rattus_norvegicus	Slc46a1	ENSRNOG00000010291

Paralogs (2): SLC46A2 (ENSG00000119457), SLC46A3 (ENSG00000139508)

Protein

Protein identifiers

Proton-coupled folate transporter — Q96NT5 (reviewed: Q96NT5)

Alternative names: Heme carrier protein 1, PCFT/HCP1, Solute carrier family 46 member 1

All UniProt accessions (5): Q96NT5, J3KTE6, J3QL21, J3QRF7, K7EPJ7

UniProt curated annotations — full annotation on UniProt →

Function. Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force. Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus. Functions at acidic pH via alternate outward- and inward-open conformation states. Protonation of residues in the outward open state primes the protein for transport. Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate. Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases. Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes. Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine. Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells. Hence, participates in the trafficking of heme and increases intracellular iron content. Inactive isoform which is not able to mediate proton-coupled folate transport.

Subunit / interactions. Monomer.

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

Tissue specificity. Expressed at highest level in the upper half of the small intestine (duodenum and jejunum), expression decreases downwardly in the subsequent quarter and is undetectable in the last quarter (the lowest ileum). Also expressed in kidney, liver, placenta, spleen, retina and retinal pigment epithelium. Lower levels found in testis. Very low levels in brain, lung, stomach, heart and muscle.

Disease relevance. Hereditary folate malabsorption (HFM) [MIM:229050] Rare autosomal recessive disorder characterized by impaired intestinal folate absorption with folate deficiency resulting in anemia, hypoimmunoglobulinemia with recurrent infections, and recurrent or chronic diarrhea. In many patients, neurological abnormalities such as seizures or intellectual disability become apparent during early childhood, attributed to impaired transport of folates into the central nervous system. When diagnosed early, the disorder can be treated by administration of folate. If untreated, it can be fatal and, if treatment is delayed, the neurological defects can become permanent. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by myricetin.

Miscellaneous. Constitutes an important route for the delivery of antifolate drugs, such as methotrexate and pemetrexed, in cancer chemotherapy. Ubiquitously expressed in solid tumors to which it delivers antifolates: within the acid microenvironment of cancer cells, antifolate drugs uptake mediated by SLC46A1/PCFT is increased.

Similarity. Belongs to the major facilitator superfamily. SLC46A family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96NT5-1	1	yes
Q96NT5-2	2

RefSeq proteins (2): NP_001229295, NP_542400* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005829	Sugar_transporter_CS	Conserved_site
IPR011701	MFS	Family
IPR020846	MFS_dom	Domain
IPR036259	MFS_trans_sf	Homologous_superfamily

Pfam: PF07690

Catalyzed reactions (Rhea), 4 shown:

• folate(in) + H(+)(in) = folate(out) + H(+)(out) (RHEA:70159)
• methotrexate(in) + H(+)(in) = methotrexate(out) + H(+)(out) (RHEA:70163)
• (6S)-5-methyl-5,6,7,8-tetrahydrofolate(in) + H(+)(in) = (6S)-5-methyl-5,6,7,8-tetrahydrofolate(out) + H(+)(out) (RHEA:70167)
• pemetrexed(in) + H(+)(in) = pemetrexed(out) + H(+)(out) (RHEA:70171)

UniProt features (81 total): mutagenesis site 27, sequence variant 14, topological domain 13, transmembrane region 12, binding site 6, modified residue 3, glycosylation site 2, chain 1, disulfide bond 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NT5-F1	82.94	0.36

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 (6): 90; 156 (reversibly protonated residue during proton transport); 185 (reversibly protonated residue during proton transport); 185; 281 (reversibly protonated residue during proton transport); 315

Post-translational modifications (3): 1, 6, 458

Disulfide bonds (1): 66–298

Glycosylation sites (2): 58, 68

Mutagenesis-validated functional residues (27):

Position	Phenotype
58	abolished n-glycosylation without affecting localization to the cell membrane; when associated with q-68.
68	abolished n-glycosylation without affecting localization to the cell membrane; when associated with q-58.
109	loss of methotrexate uptake.
109	complete loss of transport function.
156	does not affect methotrexate uptake.
156	loss of methotrexate uptake.
156	2-fold reduction of methotrexate uptake.
156	8-fold reduction of methotrexate uptake.
158	abolished sensitivity to myricetin inhibitor.
172	decreased proton-coupled folate transport.
185	abolished proton-coupled folate transport at ph 5.5 and ph 7.5.
185	abolished proton-coupled folate transport at ph 5.5, while it displays strong proton-coupled folate transporter activity
247	decreased proton-coupled folate transport.
281	abolished proton-coupled folate transport.
299	about 90% loss of transport function.
314	displays a lower affinity for folate substrate associated with a higher rate of conformational change.
315	displays a lower affinity for folate substrate associated with a higher rate of conformational change.
318	slightly decreased proton-coupled folate transport.
318	abolished proton-coupled folate transport.
376	abolishes folate uptake.
392	decreased methotrexate uptake at low concentration.
392	abolished methotrexate uptake.
392	does not affect methotrexate uptake at low concentration.
411	does not affect folate uptake.
411	abolished folate uptake.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines
R-HSA-917937	Iron uptake and transport
R-HSA-9707616	Heme signaling

MSigDB gene sets: 240 (showing top): GOBP_DIGESTION, GOBP_IRON_COORDINATION_ENTITY_TRANSPORT, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOCC_CELL_SURFACE, GOBP_IRON_ION_TRANSPORT, chr17q11, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_FOLIC_ACID_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS

GO Biological Process (12): intracellular iron ion homeostasis (GO:0006879), folic acid transport (GO:0015884), heme metabolic process (GO:0042168), tetrahydrofolate biosynthetic process (GO:0046654), folic acid metabolic process (GO:0046655), transmembrane transport (GO:0055085), intestinal folate absorption (GO:0098829), folate transmembrane transport (GO:0098838), proton transmembrane transport (GO:1902600), folate import across plasma membrane (GO:1904447), heme transport (GO:0015886), methotrexate transport (GO:0051958)

GO Molecular Function (8): folic acid binding (GO:0005542), folic acid transmembrane transporter activity (GO:0008517), proton transmembrane transporter activity (GO:0015078), heme transmembrane transporter activity (GO:0015232), symporter activity (GO:0015293), methotrexate transmembrane transporter activity (GO:0015350), transmembrane transporter activity (GO:0022857), folic acid:proton symporter activity (GO:0140211)

GO Cellular Component (9): cytoplasm (GO:0005737), endosome (GO:0005768), plasma membrane (GO:0005886), cell surface (GO:0009986), endosome membrane (GO:0010008), 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
Transport of small molecules	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
dicarboxylic acid transport	2
folic acid transport	2
nitrogen compound transport	2
dicarboxylic acid transmembrane transporter activity	2
plasma membrane region	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
vitamin transport	1
modified amino acid transport	1
porphyrin-containing compound metabolic process	1
pigment metabolic process	1
folic acid-containing compound biosynthetic process	1
tetrahydrofolate metabolic process	1
folic acid-containing compound metabolic process	1
dicarboxylic acid metabolic process	1
transport	1
cellular process	1
intestinal absorption	1
vitamin transmembrane transport	1
carboxylic acid transmembrane transport	1
monoatomic cation transmembrane transport	1
import across plasma membrane	1
folate transmembrane transport	1
iron coordination entity 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 cation transmembrane transporter activity	1
proton transmembrane transport	1
heme transport	1
transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
xenobiotic transmembrane transporter activity	1
methotrexate transport	1
transporter activity	1
transmembrane transport	1

Protein interactions and networks

STRING

792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC46A1	QDPR	P09417	819
SLC46A1	FOLR1	P15328	816
SLC46A1	SLC19A1	P41440	806
SLC46A1	HMOX1	P09601	793
SLC46A1	FOLR2	P14207	777
SLC46A1	GART	P22102	746
SLC46A1	FLVCR1	Q9Y5Y0	717
SLC46A1	SLC11A2	P49281	702
SLC46A1	CYBRD1	Q53TN4	676
SLC46A1	FOLR3	P41439	666
SLC46A1	DHFR	P00374	643
SLC46A1	DHFR2	Q86XF0	627
SLC46A1	FLVCR2	Q9UPI3	596
SLC46A1	FPGS	Q05932	596
SLC46A1	SLC48A1	Q6P1K1	593

IntAct

8 interactions, top by confidence:

A	B	Type	Score
	VAPB	psi-mi:“MI:0914”(association)	0.500
SLC46A1	SLC46A1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC46A1	EXO1	psi-mi:“MI:0915”(physical association)	0.400
	DENND11	psi-mi:“MI:0914”(association)	0.350
	NPC1	psi-mi:“MI:0914”(association)	0.350
GDPD5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
SLC46A1	MTX2	psi-mi:“MI:0914”(association)	0.350

BioGRID (26): SLC46A1 (Affinity Capture-MS), SLC46A1 (Affinity Capture-MS), SLC46A1 (Affinity Capture-MS), SLC46A1 (Affinity Capture-MS), EXO1 (Affinity Capture-MS), SLC46A1 (Affinity Capture-MS), ALDH1B1 (Affinity Capture-MS), ATL3 (Affinity Capture-MS), AUP1 (Affinity Capture-MS), CHCHD3 (Affinity Capture-MS), CHCHD6 (Affinity Capture-MS), DHCR24 (Affinity Capture-MS), GLA (Affinity Capture-MS), IMMT (Affinity Capture-MS), LGALS3 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q2HW92, A6NDV4, A6NFX1, A6QLK4, B1AWJ5, F1NCD6, F1NJ67, F1PZV2, O35308, O35595, O70461, O95907, Q08DX7, Q0IHM1, Q0P5C0, Q0P5M9, Q13286, Q14728, Q29611, Q2YDU8, Q3T9M1, Q3U481, Q501I9, Q5R8G5, Q5R9A1, Q5U419, Q60HH0, Q61124, Q66H95, Q6NUT3, Q6UXD7, Q6ZMD2, Q7RTT9, Q8BFQ6, Q8CE47, Q8NA29, Q8R0G7, Q8R139, Q8TB61, Q8VCW4

Diamond homologs: A5D7V7, F1NJ67, Q05B81, Q5BK75, Q5EBA8, Q5F4B8, Q5RBM3, Q6DCX5, Q6PEM8, Q7Z3Q1, Q7ZWG6, Q96NT5, Q9DC26, P02980, Q8NBP5, Q9D2V8, C5BC70, P45123, A0A455ZIM6, A2X8A7, B4EYY4, B8AT51, D2BX50, E3GC98, P32369, Q0JAW2, Q0P5M9, Q3EAQ5, Q6EPQ3, Q8C0T7, A0A0U2UXG3, A0A1W5T3J9, O59726, P54559, Q07282, Q14728, Q2UPC1, Q2V4F9, S7ZK48

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NRF1	“up-regulates quantity by expression”	SLC46A1	“transcriptional regulation”
SLC46A1	“up-regulates quantity”	dihydrofolate(2-)	relocalization
SLC46A1	“up-regulates quantity”	heme	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	2
Uncertain significance	109
Likely benign	82
Benign	1

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1355235	NM_080669.6(SLC46A1):c.824del (p.Phe275fs)	Pathogenic
1356258	NM_080669.6(SLC46A1):c.559_589del (p.Ile188fs)	Pathogenic
1455352	NM_080669.6(SLC46A1):c.1236_1239del (p.Leu413fs)	Pathogenic
1457240	NM_080669.6(SLC46A1):c.444_445insCTGCTGCTCCAGGCCCTAGTGTCCGTTTTTGTGGTGCAGCTGCAGCTCCACGTCGGCTACTTCGTGC (p.Ile149fs)	Pathogenic
2120585	NM_080669.6(SLC46A1):c.672_673del (p.Tyr225fs)	Pathogenic
2736487	NM_080669.6(SLC46A1):c.194dup (p.Cys66fs)	Pathogenic
2769149	NM_080669.6(SLC46A1):c.792_802dup (p.Ala268delinsGlyAsnIleTer)	Pathogenic
30924	NM_080669.6(SLC46A1):c.204_205del (p.Asn68fs)	Pathogenic
30925	NM_080669.6(SLC46A1):c.1012G>C (p.Gly338Arg)	Pathogenic
3366387	NM_080669.6(SLC46A1):c.487_493del (p.Ala163fs)	Pathogenic
851	NM_080669.6(SLC46A1):c.194del (p.Gly65fs)	Pathogenic
852	NM_080669.6(SLC46A1):c.337C>A (p.Arg113Ser)	Pathogenic
853	NM_080669.6(SLC46A1):c.954C>G (p.Ser318Arg)	Pathogenic
855	NM_080669.6(SLC46A1):c.337C>T (p.Arg113Cys)	Pathogenic
2816631	NM_080669.6(SLC46A1):c.221_228+1del	Likely pathogenic
3391327	NM_080669.6(SLC46A1):c.138T>A (p.Tyr46Ter)	Likely pathogenic

SpliceAI

1231 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28396001:G:GT	donor_gain	1.0000
17:28396027:G:GG	donor_gain	1.0000
17:28399544:C:A	donor_gain	1.0000
17:28399565:T:TA	donor_gain	1.0000
17:28399584:T:TA	donor_gain	1.0000
17:28399598:T:TA	donor_gain	1.0000
17:28402236:AC:A	donor_gain	1.0000
17:28402237:CC:C	donor_gain	1.0000
17:28402237:CCCTG:C	donor_gain	1.0000
17:28404612:TTA:T	donor_loss	1.0000
17:28404614:A:C	donor_loss	1.0000
17:28404615:CC:C	donor_loss	1.0000
17:28404655:C:CT	donor_gain	1.0000
17:28405143:T:TA	donor_gain	1.0000
17:28395900:TCCAG:T	acceptor_loss	0.9900
17:28395902:CA:C	acceptor_loss	0.9900
17:28395903:A:AG	acceptor_gain	0.9900
17:28395903:A:AT	acceptor_loss	0.9900
17:28395903:AG:A	acceptor_gain	0.9900
17:28395904:G:GA	acceptor_loss	0.9900
17:28395904:G:GG	acceptor_gain	0.9900
17:28395904:GG:G	acceptor_gain	0.9900
17:28395904:GGA:G	acceptor_gain	0.9900
17:28395904:GGAGA:G	acceptor_gain	0.9900
17:28402318:TATC:T	acceptor_gain	0.9900
17:28402320:TC:T	acceptor_gain	0.9900
17:28402321:CC:C	acceptor_gain	0.9900
17:28402322:C:CC	acceptor_gain	0.9900
17:28404656:C:CT	donor_gain	0.9900
17:28405113:G:A	donor_gain	0.9900

AlphaMissense

2936 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28405373:G:C	S108R	0.994
17:28405373:G:T	S108R	0.994
17:28405375:T:G	S108R	0.994
17:28404743:G:C	S318R	0.992
17:28404743:G:T	S318R	0.992
17:28404745:T:G	S318R	0.992
17:28404800:C:A	W299C	0.990
17:28404800:C:G	W299C	0.990
17:28404802:A:G	W299R	0.990
17:28404802:A:T	W299R	0.990
17:28400756:A:C	F392L	0.989
17:28400756:A:T	F392L	0.989
17:28400758:A:G	F392L	0.989
17:28405205:G:C	S164R	0.988
17:28405205:G:T	S164R	0.988
17:28405207:T:G	S164R	0.988
17:28405330:C:G	G123R	0.987
17:28405360:G:T	R113S	0.985
17:28405200:G:T	A166E	0.981
17:28400654:G:C	F426L	0.980
17:28400654:G:T	F426L	0.980
17:28400656:A:G	F426L	0.980
17:28402321:C:T	G361E	0.980
17:28402276:C:G	R376P	0.979
17:28405109:G:C	S196R	0.979
17:28405109:G:T	S196R	0.979
17:28405111:T:G	S196R	0.979
17:28404616:C:G	G361R	0.978
17:28404616:C:T	G361R	0.978
17:28405113:G:T	A195E	0.978

dbSNP variants (sampled 300 via entrez): RS1001300116 (17:28397956 C>T), RS1001607128 (17:28397663 C>A,G), RS1001671179 (17:28405131 C>T), RS1001805380 (17:28405639 C>T), RS1003506774 (17:28399256 C>A,G,T), RS1004082369 (17:28403938 C>G,T), RS1004881370 (17:28396780 C>T), RS1004912588 (17:28396516 G>C), RS1005551911 (17:28400186 C>A,T), RS1006352139 (17:28405824 T>C,G), RS1007922379 (17:28394967 G>C), RS1008356391 (17:28402354 G>C,T), RS1008485896 (17:28407621 C>A,T), RS1008558065 (17:28407302 T>C), RS1008846302 (17:28402001 A>G)

Disease associations

OMIM: gene MIM:611672 | disease phenotypes: MIM:229050

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary folate malabsorption	Definitive	Autosomal recessive

Mondo (2): hereditary folate malabsorption (MONDO:0009238), intellectual disability (MONDO:0001071)

Orphanet (2): Hereditary folate malabsorption (Orphanet:90045), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000155	Oral ulcer
HP:0000206	Glossitis
HP:0000708	Atypical behavior
HP:0000737	Irritability
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001880	Increased total eosinophil count
HP:0001882	Decreased total leukocyte count
HP:0001889	Megaloblastic anemia
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002020	Gastroesophageal reflux
HP:0002024	Malabsorption
HP:0002039	Anorexia
HP:0002135	Basal ganglia calcification
HP:0002205	Recurrent respiratory infections
HP:0002305	Athetosis
HP:0002514	Cerebral calcification

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002546_2	Osteoprotegerin levels	1.000000e-09
GCST006611_109	HDL cholesterol	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C562799	Folate Malabsorption, Hereditary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795188 (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)

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC46 family of folate transporters

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

Ligand	Action	Affinity	Parameter
sulfasalazine	Inhibition	4.2	pIC50
indomethacin	Inhibition	3.7	pIC50

ChEMBL bioactivities

95 potent at pChembl≥5 of 97 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.82	IC50	1.5	nM	CHEMBL4445651
8.48	IC50	3.34	nM	CHEMBL1834488
8.48	IC50	3.3	nM	CHEMBL1834488
8.42	IC50	3.82	nM	CHEMBL4538151
8.34	IC50	4.57	nM	CHEMBL4540298
8.30	IC50	5.01	nM	CHEMBL4465095
8.28	IC50	5.21	nM	CHEMBL365307
8.27	IC50	5.39	nM	CHEMBL3628344
8.27	IC50	5.4	nM	CHEMBL3628344
8.26	IC50	5.54	nM	CHEMBL4538151
8.22	IC50	6	nM	CHEMBL4465095
8.19	IC50	6.51	nM	CHEMBL3628346
8.08	IC50	8.3	nM	PEMETREXED
8.05	IC50	8.98	nM	CHEMBL4214638
8.01	IC50	9.71	nM	CHEMBL192632
7.88	IC50	13.2	nM	PEMETREXED
7.69	IC50	20.4	nM	CHEMBL4445651
7.67	IC50	21.57	nM	CHEMBL4557278
7.64	IC50	23	nM	CHEMBL192632
7.64	IC50	23	nM	CHEMBL4540298
7.52	IC50	30.4	nM	CHEMBL4214638
7.40	IC50	40	nM	CHEMBL3628344
7.38	IC50	41.5	nM	CHEMBL2158681
7.36	IC50	43.4	nM	CHEMBL590740
7.31	IC50	48.6	nM	CHEMBL4435608
7.28	IC50	53.1	nM	CHEMBL1834488
7.24	IC50	57.4	nM	CHEMBL3409336
7.24	IC50	57.6	nM	CHEMBL4214638
7.24	IC50	57	nM	PRALATREXATE
7.24	IC50	57.5	nM	CHEMBL4447805
7.17	IC50	67	nM	CHEMBL4557278
7.17	IC50	66.8	nM	PEMETREXED
7.16	Ki	70	nM	CHEMBL4445651
7.14	IC50	72.6	nM	CHEMBL2158681
7.10	IC50	80.2	nM	CHEMBL3407519
7.09	IC50	81.7	nM	CHEMBL4444011
7.09	IC50	80.45	nM	CHEMBL4761741
7.06	IC50	87.4	nM	CHEMBL4437824
7.05	IC50	88.5	nM	CHEMBL4471269
7.03	Ki	94	nM	PEMETREXED
7.02	Ki	96	nM	PEMETREXED
7.00	IC50	99.5	nM	RALTITREXED
7.00	Ki	100	nM	CHEMBL605580
6.97	IC50	107.3	nM	CHEMBL4759798
6.96	IC50	109	nM	CHEMBL4553188
6.92	IC50	120.5	nM	METHOTREXATE
6.92	IC50	121	nM	METHOTREXATE
6.92	Ki	120	nM	PEMETREXED
6.89	Ki	130	nM	CHEMBL590740
6.89	Ki	130	nM	CHEMBL1834488

PubChem BioAssay actives

95 with measured affinity, of 238 total; 37 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
(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	1512996: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0015	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	1164837: Inhibition of PCFT (unknown origin) expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0033	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-2-fluorobenzoyl]amino]pentanedioic acid	1512996: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0038	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-2-fluorobenzoyl]amino]pentanedioic acid	1512998: Binding affinity to human PCFT4 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	0.0046	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	1512998: Binding affinity to human PCFT4 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	0.0050	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]pentanedioic acid	1512998: Binding affinity to human PCFT4 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	0.0052	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	1252417: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0054	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	1252417: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0065	uM
Pemetrexed	1512996: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0083	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	1512998: Binding affinity to human PCFT4 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	0.0090	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]benzoyl]amino]pentanedioic acid	1512998: Binding affinity to human PCFT4 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	0.0097	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	1512998: Binding affinity to human PCFT4 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	0.0216	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1512996: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0415	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1197481: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0434	uM
(2S)-2-[[4-[(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)methyl-methylcarbamoyl]benzoyl]amino]pentanedioic acid	1611257: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0486	uM
Pralatrexate	1380200: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0570	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	1197481: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0574	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethoxy]benzoyl]amino]pentanedioic acid	1631982: Inhibition of human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0575	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	1197481: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0802	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-3-carbonyl]amino]pentanedioic acid	1709476: Inhibition of human PCFT expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0804	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	1631982: Inhibition of human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0817	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylamino]benzoyl]amino]pentanedioic acid	1631982: Inhibition of human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0874	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-formylamino]benzoyl]amino]pentanedioic acid	1631982: Inhibition of human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0885	uM
(2S)-2-[[5-[methyl-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methyl]amino]thiophene-2-carbonyl]amino]pentanedioic acid	1164837: Inhibition of PCFT (unknown origin) expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0995	uM
(2S)-2-[[5-[5-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)pentyl]thiophene-2-carbonyl]amino]pentanedioic acid	459866: Displacement of [3H]MTX from human PCFT expressed in Chinese hamster R2 cells at pH 5.5 by Dixon plot	ki	0.1000	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709476: Inhibition of human PCFT expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.1073	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	1631982: Inhibition of human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.1090	uM
Methotrexate	1164837: Inhibition of PCFT (unknown origin) expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.1205	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	1197481: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.1410	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluorobenzoyl]amino]pentanedioic acid	1512996: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.2070	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylsulfanyl]benzoyl]amino]pentanedioic acid	1631982: Inhibition of human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.2670	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	1197481: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.3120	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-3-carbonyl]amino]pentanedioic acid	695098: Inhibition of [3H]MTX transport at human PCFT expressed in Chinese hamster R2 cells at pH 5.5 by Dixon plot	ki	0.4200	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709476: Inhibition of human PCFT expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.4602	uM
(2S)-2-[[3-[(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)methyl-methylcarbamoyl]benzoyl]amino]pentanedioic acid	1611257: Binding affinity to human PCFT expressed in Chinese hamster R2/PCFT4 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.7470	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]hexanedioic acid	1164848: Inhibition of PCFT (unknown origin) expressed in Chinese hamster R2/PCFT4 cells assessed as reduction in PCFT-mediated [3H]MTX transport at pH 5.5 and 37 degC incubated for 5 mins	ki	1.6000	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanoic acid	1164848: Inhibition of PCFT (unknown origin) expressed in Chinese hamster R2/PCFT4 cells assessed as reduction in PCFT-mediated [3H]MTX transport at pH 5.5 and 37 degC incubated for 5 mins	ki	2.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	8
Folic Acid	decreases reaction, increases transport, decreases expression	6
Methotrexate	decreases reaction, increases transport, decreases activity, decreases expression, increases uptake (+1 more)	5
sodium arsenite	decreases expression, increases expression	3
Calcitriol	increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Sulfasalazine	decreases reaction, increases transport, decreases activity	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
5-methyltetrahydrofolate	decreases activity, decreases reaction, increases transport	1
potassium chromate(VI)	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
lometrexol	increases response to substance	1
raltitrexed	increases response to substance	1
apicidin	increases expression	1
AM 251	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
3-iodothyronamine	affects uptake	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
N-((5-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-6-yl)propyl)thiophen-2-yl)carbonyl)glutamic acid	increases uptake, increases activity, increases response to substance, decreases activity, decreases chemical synthesis (+1 more)	1
Pemetrexed	decreases reaction, increases uptake, increases activity, increases response to substance	1
Decitabine	affects expression, affects methylation	1
Sunitinib	decreases expression	1
Adenosine Triphosphate	decreases chemical synthesis, increases response to substance	1

ChEMBL screening assays

45 unique, capped per target: 45 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1067646	Binding	Displacement of [3H]MTX from human PCFT expressed in Chinese hamster R2 cells at pH 6.8 by Dixon plot	Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4PH	HCT116-SLC46A1-KO-c11	Cancer cell line	Male
CVCL_D4PI	HCT116-SLC46A1-KO-c5	Cancer cell line	Male
CVCL_TN81	HAP1 SLC46A1 (-) 1	Cancer cell line	Male
CVCL_XT32	HAP1 SLC46A1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

197 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
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
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)
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
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders