FOLR1

Summary

FOLR1 (folate receptor alpha, HGNC:3791) is a protein-coding gene on chromosome 11q13.4, encoding Folate receptor alpha (P15328). Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells.

The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 2348 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegenerative syndrome due to cerebral folate transport deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 187 total — 12 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_016729

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3791
Approved symbol	FOLR1
Name	folate receptor alpha
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	FRα
Ensembl gene	ENSG00000110195
Ensembl biotype	protein_coding
OMIM	136430
Entrez	2348

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000312293, ENST00000393676, ENST00000393679, ENST00000393681, ENST00000675784, ENST00000893310, ENST00000893311

RefSeq mRNA: 4 — MANE Select: NM_016729 NM_000802, NM_016724, NM_016725, NM_016729

CCDS: CCDS8211

Canonical transcript exons

ENST00000393676 — 4 exons

Exon	Start	End
ENSE00001516230	72192140	72192341
ENSE00002263906	72195897	72196299
ENSE00002463052	72195271	72195459
ENSE00002490205	72195612	72195747

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 99.15.

FANTOM5 (CAGE): breadth broad, TPM avg 9.4752 / max 1110.4012, expressed in 661 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115728	3.8422	431
115729	2.6744	432
115727	1.9698	294
115726	0.5447	178
115722	0.1966	62
115725	0.1549	63
115724	0.0458	19
115730	0.0280	14
115723	0.0189	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.15	gold quality
parotid gland	UBERON:0001831	98.39	gold quality
right lung	UBERON:0002167	97.02	gold quality
lower lobe of lung	UBERON:0008949	96.96	gold quality
adult mammalian kidney	UBERON:0000082	96.75	gold quality
upper lobe of lung	UBERON:0008948	96.64	gold quality
upper lobe of left lung	UBERON:0008952	96.61	gold quality
adult organism	UBERON:0007023	96.38	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.73	gold quality
trachea	UBERON:0003126	95.70	gold quality
bronchial epithelial cell	CL:0002328	95.25	gold quality
lung	UBERON:0002048	94.92	gold quality
choroid plexus epithelium	UBERON:0003911	94.46	gold quality
renal medulla	UBERON:0000362	93.89	gold quality
nephron tubule	UBERON:0001231	93.83	gold quality
epithelium of bronchus	UBERON:0002031	93.71	gold quality
bronchus	UBERON:0002185	93.68	gold quality
kidney epithelium	UBERON:0004819	92.91	gold quality
kidney	UBERON:0002113	92.65	gold quality
placenta	UBERON:0001987	91.24	gold quality
metanephros cortex	UBERON:0010533	90.68	gold quality
saliva-secreting gland	UBERON:0001044	90.62	gold quality
renal glomerulus	UBERON:0000074	90.33	gold quality
metanephric glomerulus	UBERON:0004736	89.77	gold quality
cortex of kidney	UBERON:0001225	89.33	gold quality
nasal cavity mucosa	UBERON:0001826	89.20	gold quality
left lobe of thyroid gland	UBERON:0001120	88.64	gold quality
minor salivary gland	UBERON:0001830	88.55	gold quality
thyroid gland	UBERON:0002046	88.45	gold quality
metanephros	UBERON:0000081	85.86	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	1104.00
E-MTAB-10662	yes	269.52
E-CURD-114	yes	137.26
E-MTAB-6701	yes	128.46
E-HCAD-1	yes	75.59
E-MTAB-6819	yes	49.05
E-HCAD-10	yes	29.51
E-MTAB-9388	yes	12.02
E-GEOD-130148	yes	8.78
E-MTAB-10855	no	650.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CEBPA, ESR1, ESR2, HNF1B, NCOR1, NCOR2, PGR, SP1, SP3, SP4

miRNA regulators (miRDB)

17 targeting FOLR1, 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-185-3P	99.95	67.01	1743
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-4259	95.68	65.25	582

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• findings suggest that up-regulation of FRalpha gene and calcyclin gene expressions induced by Allitridi may play an important role in human gastric cancer cell differentiation (PMID:11925593)
• The 27 kDa protein representing soluble folate binding protein exhibited a greater affinity for ligand binding than the 100 kDa protein which possesses a hydrophobic tail identical to the one that anchors the folate receptor to the cell membrane. (PMID:12516786)
• Nuclear mRNA instability due to a new ORF element determines tissue specificity of FRalpha. FR-alpha has constitutive mRNA & protein synthesis during the cell cycle & slow protein turnover, ensuring a high steady-state level to override the instability. (PMID:12612090)
• The possible anticancer agent, CB300838 has a low affinity for this carrier which makes it a possible antitumor agent. (PMID:12839949)
• Mutations in the 5’-untranslated region and proximal promoter of the folate receptor-alpha (FR-alpha) gene could be a new factor contributing to gene-food interaction explaining part of the hyperhomocysteinemia panorama. (PMID:14972645)
• Downrwegulated in an antifolate resistant leukemia cell line. (PMID:15340044)
• polymorphism may contribute to susceptibility to gastric cancer in at-risk Chinese (PMID:15754024)
• FBP secreted from epithelia of epididymis & vas deferens. A small fraction of FBP associated with prostasome-like vesicles which adhere to spermatozoa in epididymal duct. FBP may have bacteriostatic function depriving folate-requiring bacteria of folate. (PMID:16128986)
• FRalpha might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. (PMID:16453285)
• Novel mutations in the 5’-UTR of the FOLR1 gene were discovered in patients with elevated levels of homocysteine. (PMID:16475900)
• This study suggests that FR alpha plays a role in the uptake of 5-methyltetrahydrofolate when the concentration gradient is insufficient for reduced folate carrier -mediated transport. (PMID:17473184)
• intensity of folate receptor staining was strongly correlated with breast cancer outcome (PMID:17487842)
• folate receptor type beta is induced in a bone marrow engraftment model of acute myelogenous leukemia (PMID:17554378)
• Eight novel rare FOLR1 mutations with a combined prevalence of approximately 1.3% in Whites as well as two common polymorphisms with 5% and 13%, respectively, have been demonstrated. (PMID:17912458)
• Higher levels of FOLR1 appear to be associated with better prognoses for patients with lung adenocarcinomas. (PMID:18181001)
• FBP/FRalpha isoforms were demonstrated for the 1st time in human blood.These isoforms on erythrocyte membranes, in granulocytes & serum, only constituted an almost undetectable fraction of the functional FBP. The FBPalpha in neutrophils was cytoplasmic. (PMID:18588513)
• that PCFT plays a role in FRalpha-mediated endocytosis by serving as a route of export of folates from acidified endosomes (PMID:19074442)
• To determine the influence of the genotype involved in RFC1 on the response to methotrexate treatment in pediatric osteosarcomas. Altered expression of RFC1 is a feasible mechanism by which osteosarcoma cells become resistant to methotrexate. (PMID:19159907)
• FRalpha regulates pituitary tumor cell proliferation and mechanistically may involve the NOTCH pathway (PMID:19446551)
• folate receptor levels effectively differentiate ovarian carcinoma from other cancers affecting the serosal cavities (PMID:19454358)
• Results identify the presence of folate receptor alpha in normal and pathological melanocytes and demonstrated that methotrexate is preferentially transported through this receptor in melanoma cells. (PMID:19493312)
• There were no clear individual associations between methionine, vitamin B(6), or multivitamin use and ovarian cancer risk overall or by FRalpha tumor status. (PMID:19585555)
• results demonstrate that ovarian cancer patients have elevated levels of functional intact FRalpha. These findings support the potential use of circulating FRalpha as a biomarker of early ovarian cancer (PMID:19617914)
• An inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha, was identified. (PMID:19732866)
• High maternal autoantibody levels and blocking of folate binding to FRalpha in maternal serum during pregnancy are not associated with an increased risk of oral clefts in the offspring in this population-based cohort. (PMID:19952865)
• Using immunohistochemistry, FRalpha was localized to microvillous plasma membrane of syncytiotrophoblasts during first trimester and at term. (PMID:20036773)
• The rare alleles of specific single nucleotide polymorphisms within the FOLR1, FOLR2, and FOLR3 genes were statistically significant for association with meningomyelocele. (PMID:20683905)
• Since the placenta is rich in C/EBPalpha, the findings underscore the multiplicity of mechanisms by which the FRalpha gene is under the exquisite control of steroid hormones. (PMID:20817090)
• Mutation screening in the FOLR1 gene is advisable in children with profound 5MTHF deficiency and decreased CSF/serum folate ratio. (PMID:20857335)
• The expression of FOLR1 is closely related to the occurrence of nasopharyngeal carcinoma and Taxol resistance. (PMID:21215055)
• FRalpha mRNA levels were significantly higher in ovarian carcinomas compared with that of the borderline tumors. (PMID:21215165)
• Data show that the photocytotoxicity induced by folate-targeted liposomes was improved. (PMID:21215723)
• FRalpha expression is present in a subset of resected hepatic colorectal cancer metastases, and this marker is independently associated with survival (PMID:21572402)
• FR-alpha was expressed in the majority of serous ovarian tumors, although >50% of cases showed only weak expression. (PMID:21647742)
• An ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, is demonstrated. (PMID:21938430)
• FRalpha may play an important role in the development and progression of NFAs. (PMID:22089756)
• alpha-FR can be a potential biomarker for the prediction of chemotherapeutic responses and clinical prognosis. (PMID:22265591)
• PCR analysis had confirmed the existence of FR-alpha, SMVT, and B ((0, +)) in Y-79 and ARPE-19 cells. (PMID:22304562)
• studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants. (PMID:22586289)
• High folate receptor alpha is associated with adenocarcinoma in non-small-cell lung carcinoma and and EGFR [corrected] mutation. (PMID:22729036)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
danio_rerio	folr	ENSDARG00000102442

Paralogs (4): FOLR3 (ENSG00000110203), RTBDN (ENSG00000132026), FOLR2 (ENSG00000165457), IZUMO1R (ENSG00000183560)

Protein

Protein identifiers

Folate receptor alpha — P15328 (reviewed: P15328)

Alternative names: Adult folate-binding protein, Folate receptor 1, Folate receptor, adult, KB cells FBP, Ovarian tumor-associated antigen MOv18

All UniProt accessions (1): P15328

UniProt curated annotations — full annotation on UniProt →

Function. Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release. Required for normal embryonic development and normal cell proliferation.

Subcellular location. Cell membrane. Apical cell membrane. Basolateral cell membrane. Secreted. Cytoplasmic vesicle. Clathrin-coated vesicle. Endosome.

Tissue specificity. Primarily expressed in tissues of epithelial origin. Expression is increased in malignant tissues. Expressed in kidney, lung and cerebellum. Detected in placenta and thymus epithelium.

Post-translational modifications. The secreted form is derived from the membrane-bound form either by cleavage of the GPI anchor, or/and by proteolysis catalyzed by a metalloprotease.

Disease relevance. Neurodegeneration due to cerebral folate transport deficiency (NCFTD) [MIM:613068] An autosomal recessive neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the folate receptor family.

RefSeq proteins (4): NP_000793, NP_057936, NP_057937, NP_057941* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004269	Folate_rcpt	Family
IPR018143	Folate_rcpt-like	Domain

Pfam: PF03024

UniProt features (56 total): helix 11, mutagenesis site 9, disulfide bond 8, strand 7, binding site 5, turn 5, glycosylation site 3, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, propeptide 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4KM6	X-RAY DIFFRACTION	1.55
4KM7	X-RAY DIFFRACTION	1.8
4KMX	X-RAY DIFFRACTION	2.2
4LRH	X-RAY DIFFRACTION	2.8
5IZQ	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15328-F1	91.38	0.76

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 (5): 103; 107; 124–128; 157–162; 196

Post-translational modifications (1): 234

Disulfide bonds (8): 37–65, 57–105, 66–109, 89–175, 96–146, 135–209, 139–189, 152–169

Glycosylation sites (3): 161, 201, 69

Mutagenesis-validated functional residues (9):

Position	Phenotype
82	slightly reduced affinity for folate.
103	strongly reduced affinity for folate.
107	moderately reduced affinity for folate.
124	moderately reduced affinity for folate.
125	moderately reduced affinity for folate.
128	moderately reduced affinity for folate.
157	moderately reduced affinity for folate.
162	moderately reduced affinity for folate.
196	moderately reduced affinity for folate.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-5694530	Cargo concentration in the ER
R-HSA-6807878	COPI-mediated anterograde transport

MSigDB gene sets: 273 (showing top): FERRANDO_TAL1_NEIGHBORS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_SINGLE_FERTILIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, MODULE_328, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, MODULE_64, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MEMBRANE_FUSION

GO Biological Process (17): heart looping (GO:0001947), neural crest cell migration involved in heart formation (GO:0003147), cardiac neural crest cell migration involved in outflow tract morphogenesis (GO:0003253), receptor-mediated endocytosis (GO:0006898), cell adhesion (GO:0007155), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), folic acid transport (GO:0015884), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), axon regeneration (GO:0031103), sperm-egg recognition (GO:0035036), tetrahydrofolate biosynthetic process (GO:0046654), folic acid metabolic process (GO:0046655), regulation of canonical Wnt signaling pathway (GO:0060828), pharyngeal arch artery morphogenesis (GO:0061626), anterior neural tube closure (GO:0061713), cellular response to folic acid (GO:0071231), response to axon injury (GO:0048678)

GO Molecular Function (4): folic acid binding (GO:0005542), signaling receptor activity (GO:0038023), folic acid receptor activity (GO:0061714), protein binding (GO:0005515)

GO Cellular Component (19): Golgi membrane (GO:0000139), nucleus (GO:0005634), endosome (GO:0005768), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), transport vesicle (GO:0030133), clathrin-coated vesicle (GO:0030136), brush border membrane (GO:0031526), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), extracellular exosome (GO:0070062), extracellular region (GO:0005576), cytoplasmic vesicle (GO:0031410), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
neural crest cell migration	2
single fertilization	2
bounding membrane of organelle	2
endomembrane system	2
cytoplasmic vesicle	2
membrane	2
plasma membrane region	2
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
heart formation	1
cell migration involved in heart formation	1
cardiac neural crest cell development involved in heart development	1
outflow tract morphogenesis	1
cell migration involved in heart development	1
cardiac neural crest cell development involved in outflow tract morphogenesis	1
endocytosis	1
cellular process	1
cellular process involved in reproduction in multicellular organism	1
dicarboxylic acid transport	1
vitamin transport	1
modified amino acid transport	1
transforming growth factor beta receptor signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to transforming growth factor beta stimulus	1
neuron projection regeneration	1
response to axon injury	1
axon development	1
cell-cell recognition	1
folic acid-containing compound biosynthetic process	1
tetrahydrofolate metabolic process	1
folic acid-containing compound metabolic process	1
dicarboxylic acid metabolic process	1
regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
artery morphogenesis	1
pharyngeal system development	1
neural tube closure	1
tube closure	1
response to folic acid	1

Protein interactions and networks

STRING

1372 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOLR1	FOLH1	Q04609	817
FOLR1	SLC46A1	Q96NT5	816
FOLR1	PCBP1	Q15365	759
FOLR1	TYMS	P04818	720
FOLR1	EGFR	P00533	706
FOLR1	FGF3	P11487	692
FOLR1	SLC19A1	P41440	689
FOLR1	GART	P22102	684
FOLR1	TFRC	P02786	681
FOLR1	EPCAM	P16422	676
FOLR1	MSLN	Q13421	669
FOLR1	ERBB2	P04626	625
FOLR1	IZUMO1	Q8IYV9	610
FOLR1	DHFR	P00374	596
FOLR1	DHFR2	Q86XF0	575
FOLR1	MTHFR	P42898	575

IntAct

19 interactions, top by confidence:

A	B	Type	Score
FOLR1	SLC35F6	psi-mi:“MI:0915”(physical association)	0.560
Cbx1	FLOT1	psi-mi:“MI:0915”(physical association)	0.400
Dync1h1	DYNLT3	psi-mi:“MI:0915”(physical association)	0.400
Cdk1		psi-mi:“MI:0915”(physical association)	0.400
Poc1b		psi-mi:“MI:0915”(physical association)	0.400
Cep192	AURKA	psi-mi:“MI:0915”(physical association)	0.400
Trim69		psi-mi:“MI:0915”(physical association)	0.400
Cep76	DCTN2	psi-mi:“MI:0915”(physical association)	0.400
	RAP1BL	psi-mi:“MI:0915”(physical association)	0.400
FOLR1	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370
FOLR1	CUL3	psi-mi:“MI:0915”(physical association)	0.370
FOLR1	IRAK3	psi-mi:“MI:0915”(physical association)	0.370
NCAPH2	FOLR1	psi-mi:“MI:0915”(physical association)	0.370
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
FOLR1	GPC3	psi-mi:“MI:0914”(association)	0.350
SLC35F6	FOLR1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (234): SLC35F6 (Two-hybrid), FOLR1 (Affinity Capture-MS), FOLR1 (Affinity Capture-MS), FOLR1 (Affinity Capture-MS), FOLR1 (Affinity Capture-MS), FOLR1 (Affinity Capture-MS), FOLR1 (Two-hybrid), FOLR1 (Affinity Capture-MS), FOLR1 (Affinity Capture-MS), FOLR1 (Affinity Capture-MS), LCLAT1 (Affinity Capture-MS), GPC3 (Affinity Capture-MS), FOLR1 (Affinity Capture-MS), PHB (Affinity Capture-Western), PHB2 (Affinity Capture-Western)

ESM2 similar proteins: A0A3Q1LRJ2, A6ND01, B8JI67, E1B9E5, F1M928, O15547, P02702, P02752, P0DJF3, P0DN42, P10820, P14207, P15328, P16229, P27767, P35846, P41439, P48251, P51653, P86009, Q05685, Q3HRV3, Q3S2X5, Q3UPR9, Q3V5L5, Q4TUC0, Q5EA85, Q5FB95, Q5M936, Q62178, Q62190, Q64663, Q64716, Q6DFV8, Q765H6, Q7TPG6, Q7Z5A8, Q8BMN4, Q8IVN8, Q8N2E2

Diamond homologs: A6ND01, F1M928, P02702, P02752, P14207, P15328, P35846, P41439, P86009, Q05685, Q9EQF4, Q5DRQ5, P85896

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOLR1	“up-regulates quantity”	(6S)-5-methyltetrahydrofolate(2-)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	7
Uncertain significance	75
Likely benign	61
Benign	12

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1322929	NM_016729.3(FOLR1):c.258G>A (p.Trp86Ter)	Pathogenic
1459015	NC_000011.9:g.(?71903218)(71903405_?)del	Pathogenic
1459749	NM_016729.3(FOLR1):c.330_333dup (p.Asn112fs)	Pathogenic
16255	NM_016729.3(FOLR1):c.352C>T (p.Gln118Ter)	Pathogenic
16256	NM_016729.3(FOLR1):c.525C>A (p.Cys175Ter)	Pathogenic
2024511	NM_016729.3(FOLR1):c.321C>A (p.Tyr107Ter)	Pathogenic
2426313	NC_000011.9:g.(?71903218)(72019668_?)del	Pathogenic
2501867	NM_016729.3(FOLR1):c.227del (p.Lys76fs)	Pathogenic
3244663	NC_000011.9:g.(?71906295)(71907221_?)del	Pathogenic
470723	NM_016729.3(FOLR1):c.257G>A (p.Trp86Ter)	Pathogenic
501379	NM_016729.3(FOLR1):c.34del (p.Leu12fs)	Pathogenic
929424	NM_016729.3(FOLR1):c.197G>A (p.Cys66Tyr)	Pathogenic
1012987	NM_016729.3(FOLR1):c.494-2A>G	Likely pathogenic
3571466	NM_016729.3(FOLR1):c.134_143del (p.Glu45fs)	Likely pathogenic
372855	NM_016729.3(FOLR1):c.357+1G>A	Likely pathogenic
373986	NM_016729.3(FOLR1):c.287G>A (p.Cys96Tyr)	Likely pathogenic
3892365	NM_016729.3(FOLR1):c.172C>T (p.Arg58Ter)	Likely pathogenic
393190	NM_016729.3(FOLR1):c.1A>G (p.Met1Val)	Likely pathogenic
429907	NM_016729.3(FOLR1):c.610C>T (p.Arg204Ter)	Likely pathogenic

SpliceAI

592 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72195266:T:G	acceptor_gain	1.0000
11:72195269:A:AG	acceptor_gain	1.0000
11:72195270:G:GA	acceptor_gain	1.0000
11:72195270:GT:G	acceptor_gain	1.0000
11:72195270:GTGTC:G	acceptor_gain	1.0000
11:72195456:GCAG:G	donor_gain	1.0000
11:72195459:GGTA:G	donor_loss	1.0000
11:72195461:T:G	donor_loss	1.0000
11:72195600:A:AG	acceptor_gain	1.0000
11:72195601:A:G	acceptor_gain	1.0000
11:72195602:A:G	acceptor_gain	1.0000
11:72195603:A:G	acceptor_gain	1.0000
11:72195604:T:G	acceptor_gain	1.0000
11:72195606:A:AG	acceptor_gain	1.0000
11:72195607:C:G	acceptor_gain	1.0000
11:72195608:CCAG:C	acceptor_loss	1.0000
11:72195609:CA:C	acceptor_loss	1.0000
11:72195610:A:AC	acceptor_loss	1.0000
11:72195610:AGGT:A	acceptor_gain	1.0000
11:72195611:G:A	acceptor_loss	1.0000
11:72195611:GGT:G	acceptor_gain	1.0000
11:72195611:GGTG:G	acceptor_gain	1.0000
11:72195745:CAG:C	donor_loss	1.0000
11:72195749:T:A	donor_loss	1.0000
11:72195893:ACAG:A	acceptor_gain	1.0000
11:72195895:AG:A	acceptor_gain	1.0000
11:72195896:GG:G	acceptor_gain	1.0000
11:72195265:A:AG	acceptor_gain	0.9900
11:72195267:CCA:C	acceptor_loss	0.9900
11:72195268:CA:C	acceptor_loss	0.9900

AlphaMissense

1710 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72195680:G:C	W142C	0.992
11:72195680:G:T	W142C	0.992
11:72196043:T:C	F214L	0.991
11:72196045:C:A	F214L	0.991
11:72196045:C:G	F214L	0.991
11:72195282:G:C	W60C	0.990
11:72195282:G:T	W60C	0.990
11:72195450:G:C	W116C	0.990
11:72195450:G:T	W116C	0.990
11:72195722:G:C	W156C	0.990
11:72195722:G:T	W156C	0.990
11:72195683:G:C	W143C	0.987
11:72195683:G:T	W143C	0.987
11:72195313:A:C	S71R	0.985
11:72195315:C:A	S71R	0.985
11:72195315:C:G	S71R	0.985
11:72195734:G:C	W160C	0.983
11:72195734:G:T	W160C	0.983
11:72195352:T:C	F84L	0.982
11:72195354:C:A	F84L	0.982
11:72195354:C:G	F84L	0.982
11:72195448:T:A	W116R	0.981
11:72195448:T:C	W116R	0.981
11:72196044:T:G	F214C	0.980
11:72195401:T:G	F100C	0.979
11:72195427:T:A	C109S	0.977
11:72195428:G:C	C109S	0.977
11:72195626:G:C	W124C	0.977
11:72195626:G:T	W124C	0.977
11:72195982:G:C	W193C	0.976

dbSNP variants (sampled 300 via entrez): RS1000085998 (11:72196367 T>C), RS1000285936 (11:72196766 T>C,G), RS1002142997 (11:72192987 C>T), RS1002410435 (11:72192809 C>T), RS1003454532 (11:72193449 CTT>C,CT,CTTT,CTTTT), RS1003530084 (11:72192045 G>A,T), RS1003622027 (11:72193692 C>G,T), RS1003961837 (11:72193342 G>A), RS1004035358 (11:72193065 C>T), RS1004126685 (11:72190527 G>T), RS1005561299 (11:72193768 A>G), RS1005636400 (11:72192021 G>A,T), RS1005708408 (11:72191626 T>C), RS1005890697 (11:72195354 C>A), RS1005970503 (11:72190619 A>C)

Disease associations

OMIM: gene MIM:136430 | disease phenotypes: MIM:613068, MIM:606764

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegenerative syndrome due to cerebral folate transport deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodegenerative syndrome due to cerebral folate transport deficiency	Definitive	AR

Mondo (2): neurodegenerative syndrome due to cerebral folate transport deficiency (MONDO:0013110), gastrointestinal stromal tumor (MONDO:0011719)

Orphanet (2): Neurodegenerative syndrome due to cerebral folate transport deficiency (Orphanet:217382), Gastrointestinal stromal tumor (Orphanet:44890)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0002180	Neurodegeneration
HP:0002376	Developmental regression

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D046152	Gastrointestinal Stromal Tumors	C04.557.450.565.370; C06.301.371.308; C06.405.249.308
C567791	Neurodegeneration Due To Cerebral Folate Transport Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2121 (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: other protein — Tumour-associated antigens

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

Ligand	Action	Affinity	Parameter
mirvetuximab soravtansine	Binding	10.1	pKd

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4866304	IC50	6.9 nM

ChEMBL bioactivities

84 potent at pChembl≥5 of 84 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.85	IC50	0.14	nM	CHEMBL4445651
9.81	Kd	0.153	nM	CHEMBL85871
9.51	IC50	0.31	nM	CHEMBL1834488
9.48	IC50	0.33	nM	CHEMBL3628344
9.47	IC50	0.34	nM	CHEMBL4790375
9.44	IC50	0.36	nM	CHEMBL4465095
9.42	IC50	0.38	nM	CHEMBL1834488
9.42	Kd	0.38	nM	CHEMBL84935
9.36	IC50	0.44	nM	CHEMBL4759798
9.29	IC50	0.51	nM	CHEMBL4467936
9.24	IC50	0.58	nM	CHEMBL4540298
9.24	Kd	0.57	nM	CHEMBL309415
9.21	IC50	0.61	nM	CHEMBL3628346
9.16	IC50	0.69	nM	CHEMBL4557278
9.16	Kd	0.69	nM	CHEMBL82390
9.04	IC50	0.91	nM	CHEMBL4783397
9.02	Kd	0.95	nM	CHEMBL82261
8.97	IC50	1.08	nM	CHEMBL4553188
8.97	IC50	1.08	nM	CHEMBL4761741
8.95	IC50	1.12	nM	CHEMBL4538151
8.90	IC50	1.27	nM	CHEMBL4214638
8.89	IC50	1.3	nM	CHEMBL4214638
8.85	IC50	1.4	nM	CHEMBL4441626
8.85	IC50	1.4	nM	CHEMBL4435608
8.85	IC50	1.4	nM	CHEMBL4852455
8.75	IC50	1.78	nM	CHEMBL4562619
8.74	IC50	1.82	nM	CHEMBL590740
8.72	IC50	1.89	nM	CHEMBL4447805
8.60	IC50	2.5	nM	CHEMBL2158681
8.59	IC50	2.55	nM	CHEMBL4741259
8.52	IC50	3.04	nM	CHEMBL4437824
8.52	IC50	3.01	nM	CHEMBL4471269
8.39	IC50	4.1	nM	CHEMBL192632
8.35	IC50	4.43	nM	CHEMBL4213181
8.31	IC50	4.87	nM	CHEMBL4444011
8.25	IC50	5.62	nM	CHEMBL4755197
8.20	IC50	6.3	nM	CHEMBL365307
8.18	IC50	6.6	nM	CHEMBL3335604
8.16	IC50	6.9	nM	CHEMBL4866304
8.11	IC50	7.78	nM	CHEMBL4515056
8.05	IC50	9	nM	CHEMBL491104
8.02	IC50	9.5	nM	CHEMBL3335605
7.99	Kd	10.3	nM	CHEMBL5647334
7.98	IC50	10.5	nM	CHEMBL4789686
7.85	Kd	14.2	nM	CHEMBL5646761
7.82	IC50	15	nM	RALTITREXED
7.82	IC50	15.02	nM	CHEMBL4205344
7.66	Kd	22.1	nM	CHEMBL5641722
7.56	IC50	27.4	nM	CHEMBL3335606
7.40	Kd	39.8	nM	CHEMBL5639825

PubChem BioAssay actives

87 with measured affinity, of 190 total; 50 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-[[5-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]thiophene-2-carbonyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	<0.0001	uM
(2R)-2-[[5-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]thiophene-2-carbonyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	<0.0001	uM
2-[[4-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]benzoyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	<0.0001	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	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0001	uM
(2S)-2-[[5-[3-[(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)sulfanyl]propyl]thiophene-2-carbonyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	0.0002	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	1164833: Inhibition of FRalpha (unknown origin) expressed in Chinese hamster RT16 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0003	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	1252413: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0003	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0003	uM
(2S)-2-[[5-[3-[(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)sulfanyl]propyl]-3-methylthiophene-2-carbonyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	0.0004	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	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0004	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0004	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylsulfanyl]benzoyl]amino]pentanedioic acid	1631980: Inhibition of human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0005	uM
(2S)-2-[[6-[(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)sulfanylmethyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carbonyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	0.0006	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	1252413: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0006	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-2-fluorobenzoyl]amino]pentanedioic acid	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0006	uM
(2S)-2-[[5-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]-4-methylthiophene-2-carbonyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	0.0007	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	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0007	uM
(2R)-2-[[5-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]-4-methylthiophene-2-carbonyl]amino]pentanedioic acid	71207: compound was tested for the ability to function as transport substrates for the human folate-binding protein(mFBP)	kd	0.0009	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-3-carbonyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0009	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-2-fluorobenzoyl]amino]pentanedioic acid	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0011	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	1631980: Inhibition of human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0011	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]thiophene-3-carbonyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0011	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	1380197: Binding affinity to human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0013	uM
(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]-5-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-3-carboxy-1-[[(1R)-1-carboxy-2-sulfanylethyl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1763694: Displacement of [3H]-folic acid from FRalpha (unknown origin) expressed in human KB cells after 1 hr	ic50	0.0014	uM
(2S)-2-[[4-[(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)methyl-methylcarbamoyl]benzoyl]amino]pentanedioic acid	1611256: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0014	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluorobenzoyl]amino]pentanedioic acid	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0014	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	1197480: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as cell growth inhibition after 96 hrs by CellTiter-Blue assay	ic50	0.0018	uM
(2S)-2-[[3-[(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)methyl-methylcarbamoyl]benzoyl]amino]pentanedioic acid	1611256: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0018	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethoxy]benzoyl]amino]pentanedioic acid	1631980: Inhibition of human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0019	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	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0025	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0026	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylamino]benzoyl]amino]pentanedioic acid	1631980: Inhibition of human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0030	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-formylamino]benzoyl]amino]pentanedioic acid	1631980: Inhibition of human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0030	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]benzoyl]amino]pentanedioic acid	1512994: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0041	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]pyridine-2-carbonyl]amino]pentanedioic acid	1380197: Binding affinity to human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0044	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	1631980: Inhibition of human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue fluorescence analysis	ic50	0.0049	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0056	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]pentanedioic acid	1380197: Binding affinity to human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0063	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]butanedioic acid	1164833: Inhibition of FRalpha (unknown origin) expressed in Chinese hamster RT16 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0066	uM
(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]-5-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[(2S)-3-carboxy-1-[[(2S)-3-carboxy-1-[[(1R)-1-carboxy-2-[2-[(1R,3R,8R,12S,13R,18E,20Z,24R,25S,26S)-5,13,25-trimethyl-11,17,22-trioxospiro[2,10,16,23-tetraoxatetracyclo[22.2.1.03,8.08,25]heptacosa-4,18,20-triene-26,2’-oxirane]-12-yl]oxycarbonyloxyethyldisulfanyl]ethyl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1763694: Displacement of [3H]-folic acid from FRalpha (unknown origin) expressed in human KB cells after 1 hr	ic50	0.0069	uM
(2S)-2-[[5-[(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)methyl-methylcarbamoyl]thiophene-2-carbonyl]amino]pentanedioic acid	1611256: Binding affinity to human FRalpha expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0078	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0090	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	1164833: Inhibition of FRalpha (unknown origin) expressed in Chinese hamster RT16 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0095	uM
4-[(2E)-2-[(2E)-2-[2-[4-[(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]-2-carboxyethyl]phenoxy]-3-[(E)-2-[3,3-dimethyl-1-(4-sulfobutyl)indol-1-ium-2-yl]ethenyl]cyclohex-2-en-1-ylidene]ethylidene]-3,3-dimethylindol-1-yl]butane-1-sulfonate	2143766: Binding affinity to Folate receptor alpha in human KB cells assessed as dissociation constant	kd	0.0103	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]furan-2-carbonyl]amino]pentanedioic acid	1709474: Inhibition of human FRalpha expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in cell proliferation after 96 hrs by CellTiter-blue assay	ic50	0.0105	uM
4-[(2E)-2-[(2E)-2-[2-[4-[(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]-2-carboxyethyl]phenoxy]-3-[(E)-2-[3,3-dimethyl-1-(4-sulfobutyl)indol-1-ium-2-yl]ethenyl]cyclohex-2-en-1-ylidene]ethylidene]-3,3-dimethylindol-1-yl]butane-1-sulfonate	2143766: Binding affinity to Folate receptor alpha in human KB cells assessed as dissociation constant	kd	0.0142	uM
(2S)-2-[[5-[methyl-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methyl]amino]thiophene-2-carbonyl]amino]pentanedioic acid	1164833: Inhibition of FRalpha (unknown origin) expressed in Chinese hamster RT16 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0150	uM
(2S)-2-[[6-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]pyridine-3-carbonyl]amino]pentanedioic acid	1380197: Binding affinity to human FR-alpha receptor expressed in Chinese hamster RT16 cells assessed as antiproliferative activity measured as reduction in cell viability after 96 hrs by Cell-Titer Blue assay	ic50	0.0150	uM
4-[(2E)-2-[(2E)-2-[2-[4-[(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]-2-carboxyethyl]phenoxy]-3-[(E)-2-[3,3-dimethyl-1-(4-sulfobutyl)indol-1-ium-2-yl]ethenyl]cyclohex-2-en-1-ylidene]ethylidene]-3,3-dimethylindol-1-yl]butane-1-sulfonate	2143766: Binding affinity to Folate receptor alpha in human KB cells assessed as dissociation constant	kd	0.0221	uM
4-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]butanoic acid	1164833: Inhibition of FRalpha (unknown origin) expressed in Chinese hamster RT16 cells assessed as cell growth inhibition incubated up to 96 hrs by Celltiter-blue cell viability assay	ic50	0.0274	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Folic Acid	decreases abundance, increases expression, increases phosphorylation, increases transport, affects binding (+6 more)	9
Valproic Acid	decreases expression, increases acetylation, increases methylation, affects cotreatment, increases expression (+1 more)	8
Estradiol	affects cotreatment, increases expression, decreases expression	4
bisphenol A	decreases expression	2
sodium arsenite	affects expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Ethanol	decreases expression, increases expression	2
Doxorubicin	decreases expression, decreases response to substance	2
Hydrogen Peroxide	affects expression, affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Progesterone	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
biochanin A	decreases expression	1
methylmercuric chloride	decreases expression, increases expression	1
5-methyltetrahydrofolate	increases uptake	1
glycidyl methacrylate	decreases expression	1
trichostatin A	increases expression	1
o,p’-DDT	decreases expression	1
sulforaphane	decreases expression	1
perfluorooctanoic acid	decreases expression	1
diallyl trisulfide	increases expression	1
pentanal	increases expression	1
raltitrexed	increases response to substance	1
CGP 52608	affects binding, increases reaction	1
apicidin	increases expression	1

ChEMBL screening assays

34 unique, capped per target: 34 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003024	Binding	Displacement of [3H]folic acid from human folate receptor alpha in chinese hamster RT16 cells assessed as relative binding affinity relative to folic acid	Synthesis and biological activity of a novel series of 6-substituted thieno[2,3-d]pyrimidine antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors over the reduced folate carrier and proton-coupled folate transporter for cellular entry. — J Med Chem

Cellosaurus cell lines

16 cell lines: 8 cancer cell line, 4 transformed cell line, 2 spontaneously immortalized cell line, 1 induced pluripotent stem cell, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1SA	Abcam HeLa FOLR1 KO	Cancer cell line	Female
CVCL_B8G8	Abcam HCT 116 FOLR1 KO	Cancer cell line	Male
CVCL_B9IH	Abcam A-549 FOLR1 KO	Cancer cell line	Male
CVCL_C7LX	GM28577	Induced pluripotent stem cell	Female
CVCL_D2F5	Abcam MCF-7 FOLR1 KO	Cancer cell line	Female
CVCL_D8LJ	Ubigene HCT 116 FOLR1 KO	Cancer cell line	Male
CVCL_E0D7	Ubigene HeLa FOLR1 KO	Cancer cell line	Female
CVCL_E6AJ	CHO-FOLR1	Spontaneously immortalized cell line	Female
CVCL_E6AK	HEK293-FOLR1	Transformed cell line	Female
CVCL_E6QH	Genomeditech CHO-K1 H_FOLR1	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00171977	PHASE4	COMPLETED	Post-Marketing Clinical Study of Postoperative Adjuvant Therapy With Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT00510354	PHASE4	COMPLETED	Treatment of Patients With Everolimus and Imatinib Mesylate Who Have Progressive Gastro Intestinal Stromal Tumors (GIST) and Are Resistant to Imatinib Mesylate
NCT00756509	PHASE4	COMPLETED	Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT02800330	PHASE4	COMPLETED	The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib
NCT04825574	PHASE4	COMPLETED	Study for Patients Previously Treated in Avapritinib Clinical Trials
NCT00009906	PHASE3	TERMINATED	Comparison of Two Different Doses of STI571 in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00041197	PHASE3	COMPLETED	Imatinib Mesylate in Treating Patients With Primary Gastrointestinal Stromal Tumor That Has Been Completely Removed By Surgery
NCT00075218	PHASE3	COMPLETED	A Study To Assess The Safety And Efficacy Of SU11248 In Patients With Gastrointestinal Stromal Tumor(GIST)
NCT00103168	PHASE3	COMPLETED	Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor
NCT00293124	PHASE3	COMPLETED	Open-label Trial of GlivecWith Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors
NCT00324987	PHASE3	TERMINATED	Imatinib Mesylate With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00372567	PHASE3	TERMINATED	Safety And Effectiveness Of Daily Dosing With Sunitinib Or Imatinib In Patients With Gastrointestinal Stromal Tumors
NCT00471328	PHASE3	COMPLETED	Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib
NCT00685828	PHASE3	UNKNOWN	Imatinib Mesylate in Treating Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumor
NCT00688766	PHASE3	TERMINATED	Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib
NCT00751036	PHASE3	TERMINATED	Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
NCT00785785	PHASE3	COMPLETED	A Study of Nilotinib Versus Imatinib in GIST Patients
NCT00812240	PHASE3	TERMINATED	Masitinib in First Line Treatment of Gastro-Intestinal Stromal Tumor (GIST)
NCT00956072	PHASE3	TERMINATED	Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate
NCT01031628	PHASE3	TERMINATED	Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients
NCT01151852	PHASE3	COMPLETED	Rechallenge of Imatinib in GIST Having no Effective Treatment: RIGHT
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01271712	PHASE3	COMPLETED	Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
NCT01289028	PHASE3	COMPLETED	Efficacy of Nilotinib in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Imatinib and Sunitinib.
NCT01462994	PHASE3	COMPLETED	Detection of CF-DNA in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT01694277	PHASE3	COMPLETED	Masitinib in Patients With Gastrointestinal Stromal Tumour After Progression With Imatinib
NCT02260505	PHASE3	COMPLETED	Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)
NCT02576080	PHASE3	UNKNOWN	Efficacy of Imatinib in Patients With Intermediate-risk Gastrointestinal Stromal Tumor With a High-risk Genomic Grade Index
NCT02866045	PHASE3	UNKNOWN	EUS-FNB vs. Single-incision Needle-knife (SINK) Biopsy for Gastrointestinal SELs
NCT03353753	PHASE3	COMPLETED	Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies
NCT03426722	PHASE3	COMPLETED	L-carnitine vs Placebo for the Treatment of Muscle Cramps After Imatinib in Gastrointestinal Stromal Tumors
NCT03465722	PHASE3	COMPLETED	(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST
NCT03673501	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib
NCT04409223	PHASE3	TERMINATED	Efficacy and Safety of Famitinib Versus Sunitinib in the Treatment of Advanced Gastrointestinal Stromal Tumour Patients After Failure of Imatinib
NCT05208047	PHASE3	ACTIVE_NOT_RECRUITING	(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors
NCT05734105	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Patients With Advanced GIST With Specific KIT Exon Mutations Who Were Previously Treated With Imatinib
NCT06640361	PHASE3	RECRUITING	A Study of Olverembatinib in SDH-deficient GIST.
NCT07585266	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (StrateGIST Frontline)
NCT00003939	PHASE2	COMPLETED	Ecteinascidin 743 in Treating Patients With Advanced Soft Tissue Sarcoma