FOLR3

Summary

FOLR3 (folate receptor gamma, HGNC:3795) is a protein-coding gene on chromosome 11q13.4, encoding Folate receptor gamma (P41439). Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells.

This gene encodes a member of the folate receptor (FOLR) family of proteins, which have a high affinity for folic acid and for several reduced folic acid derivatives, and mediate delivery of 5-methyltetrahydrofolate to the interior of cells. Expression of this gene may be elevated in ovarian and primary peritoneal carcinoma. This gene is present in a gene cluster on chromosome 11. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2352 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_000804

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3795
Approved symbol	FOLR3
Name	folate receptor gamma
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	FR-G, FRγ
Ensembl gene	ENSG00000110203
Ensembl biotype	protein_coding
OMIM	602469
Entrez	2352

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000545379, ENST00000546166, ENST00000611028, ENST00000612844, ENST00000622388, ENST00000897859, ENST00000897860, ENST00000946849, ENST00000946850

RefSeq mRNA: 2 — MANE Select: NM_000804 NM_000804, NM_001412270

CCDS: CCDS73344

Canonical transcript exons

ENST00000611028 — 5 exons

Exon	Start	End
ENSE00001267095	72135947	72136120
ENSE00003735859	72139347	72139482
ENSE00003738872	72139587	72139892
ENSE00003752652	72135725	72135768
ENSE00003752856	72138961	72139149

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 92.50.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6922 / max 452.2166, expressed in 413 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115720	0.9364	93
115716	0.8682	274
115717	0.3582	75
115719	0.3522	65
115718	0.1772	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	92.50	gold quality
blood	UBERON:0000178	91.20	gold quality
monocyte	CL:0000576	89.77	gold quality
bone marrow	UBERON:0002371	89.51	gold quality
mononuclear cell	CL:0000842	89.32	gold quality
leukocyte	CL:0000738	89.26	gold quality
stromal cell of endometrium	CL:0002255	88.70	gold quality
spleen	UBERON:0002106	84.82	gold quality
bone marrow cell	CL:0002092	84.47	gold quality
trabecular bone tissue	UBERON:0002483	79.35	gold quality
adult mammalian kidney	UBERON:0000082	79.11	gold quality
triceps brachii	UBERON:0001509	77.24	gold quality
gluteal muscle	UBERON:0002000	77.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.03	gold quality
metanephros cortex	UBERON:0010533	74.77	gold quality
periodontal ligament	UBERON:0008266	72.77	gold quality
upper lobe of left lung	UBERON:0008952	71.59	gold quality
tongue squamous epithelium	UBERON:0006919	70.62	gold quality
kidney	UBERON:0002113	70.58	gold quality
upper lobe of lung	UBERON:0008948	70.30	gold quality
right lung	UBERON:0002167	69.67	gold quality
nasal cavity epithelium	UBERON:0005384	68.66	gold quality
heart right ventricle	UBERON:0002080	68.17	gold quality
olfactory bulb	UBERON:0002264	67.98	gold quality
type B pancreatic cell	CL:0000169	67.72	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.72	gold quality
Brodmann (1909) area 46	UBERON:0006483	67.54	gold quality
vastus lateralis	UBERON:0001379	67.19	gold quality
cortex of kidney	UBERON:0001225	66.61	gold quality
renal medulla	UBERON:0000362	66.57	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-55	yes	2084.63
E-ANND-3	yes	11.13
E-CURD-112	yes	8.81
E-MTAB-9801	yes	6.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

Literature-anchored findings (GeneRIF, showing 7)

• The rare alleles of specific single nucleotide polymorphisms within the FOLR1, FOLR2, and FOLR3 genes were statistically significant for association with meningomyelocele. (PMID:20683905)
• We identified eight novel variants in SLC19A1 and twelve novel variants in FOLR1, FOLR2, and FOLR3. Pathogenic variants include c.1265delG in SLC19A1 resulting in an early stop codon, four large insertion deletion variants in FOLR3, and a stop_gain variant in FOLR3 (PMID:28948692)
• Plasma Homocysteine Concentration is Associated with the Expression Level of Folate Receptor 3. (PMID:32581311)
• A folate receptor 3 SNP promotes mitochondria-induced clonogenicity of CML leukemia cells: Implications for treatment free remission. (PMID:33634983)
• A Novel Immunomodulatory Mechanism by Which Vitamin D Influences Folate Receptor 3 Expression to Reduce COVID-19 Severity. (PMID:36192006)
• Secreted folate receptor gamma drives fibrogenesis in metabolic dysfunction-associated steatohepatitis by amplifying TGFbeta signaling in hepatic stellate cells. (PMID:37756380)
• Blood FOLR3 methylation dysregulations and heterogeneity in non-small lung cancer highlight its strong associations with lung squamous carcinoma. (PMID:38273401)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
danio_rerio	folr	ENSDARG00000102442

Paralogs (4): FOLR1 (ENSG00000110195), RTBDN (ENSG00000132026), FOLR2 (ENSG00000165457), IZUMO1R (ENSG00000183560)

Protein

Protein identifiers

Folate receptor gamma — P41439 (reviewed: P41439)

Alternative names: Folate receptor 3

All UniProt accessions (3): P41439, A0A087WYI3, F5H2G8

UniProt curated annotations — full annotation on UniProt →

Function. Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells. Isoform Short does not bind folate.

Subcellular location. Secreted.

Tissue specificity. Spleen, thymus, bone marrow, ovarian carcinoma, and uterine carcinoma.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Variant in position: 150:MSAHPTWGPGSGRSTRAGAKSAF->ECSPNLGPWIRQVNQSWRKERILNVPLCKEDCERW WEDCRTSYTCKSNWHKGWNWTSGINECPAGALCSTFESYFPTPAALCEGLWSHSFKVSNYSRG.

Similarity. Belongs to the folate receptor family.

Isoforms (2)

UniProt ID	Names	Canonical?
P41439-1	1, Long	yes
P41439-4	2

RefSeq proteins (2): NP_000795, NP_001399199 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004269	Folate_rcpt	Family
IPR018143	Folate_rcpt-like	Domain

Pfam: PF03024

UniProt features (23 total): disulfide bond 8, binding site 5, glycosylation site 3, splice variant 2, sequence conflict 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41439-F1	90.27	0.79

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

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

Glycosylation sites (3): 121, 161, 201

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 91 (showing top): GOBP_SINGLE_FERTILIZATION, MODULE_328, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, MODULE_64, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOCC_CELL_SURFACE, chr11q13, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_SPERM_EGG_RECOGNITION, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_DICARBOXYLIC_ACID_TRANSPORT

GO Biological Process (4): cell adhesion (GO:0007155), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), folic acid transport (GO:0015884), sperm-egg recognition (GO:0035036)

GO Molecular Function (3): folic acid binding (GO:0005542), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), external side of plasma membrane (GO:0009897), membrane (GO:0016020), extrinsic component of membrane (GO:0019898), specific granule lumen (GO:0035580), tertiary granule lumen (GO:1904724)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
single fertilization	2
cellular process	1
cellular process involved in reproduction in multicellular organism	1
dicarboxylic acid transport	1
vitamin transport	1
modified amino acid transport	1
cell-cell recognition	1
vitamin binding	1
carboxylic acid binding	1
modified amino acid binding	1
heterocyclic compound binding	1
molecular transducer activity	1
binding	1
plasma membrane	1
cell surface	1
side of membrane	1
membrane	1
secretory granule lumen	1
specific granule	1
intracellular organelle lumen	1
tertiary granule	1

Protein interactions and networks

STRING

826 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOLR3	FOLH1	Q04609	798
FOLR3	TFRC	P02786	688
FOLR3	EGFR	P00533	685
FOLR3	SLC46A1	Q96NT5	666
FOLR3	CD44	P16070	591
FOLR3	IZUMO1	Q8IYV9	573
FOLR3	ERBB2	P04626	571
FOLR3	EPCAM	P16422	560
FOLR3	SLC19A1	P41440	536
FOLR3	MUC1	P13931	534
FOLR3	TCN1	P20061	518
FOLR3	MTHFR	P42898	518
FOLR3	SLC25A32	Q9H2D1	515
FOLR3	MSLN	Q13421	507
FOLR3	GART	P22102	480

IntAct

8 interactions, top by confidence:

A	B	Type	Score
FOLR3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
FOLR3	ANKRD11	psi-mi:“MI:0915”(physical association)	0.560
FOLR3	FOLR2	psi-mi:“MI:0914”(association)	0.350
UBQLN1	FOLR3	psi-mi:“MI:0915”(physical association)	0.000
ANKRD11	FOLR3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): UBQLN1 (Two-hybrid), ANKRD11 (Two-hybrid), FOLR2 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), FOLR3 (Two-hybrid), FOLR3 (Two-hybrid)

ESM2 similar proteins: A2X2H7, A2XHZ9, A9SV59, F4HXW9, F4IAX0, F4IAX1, O04500, O23349, O80844, P0DO00, P41439, P45582, P50699, P51577, Q0DZ85, Q10JL1, Q10NX8, Q53MB8, Q5DWG1, Q5E9U1, Q5N8X6, Q60E70, Q6Z4G7, Q6Z4G8, Q6Z6K4, Q75IW1, Q7XR91, Q84TW8, Q8GZ17, Q8H1E6, Q8H1H9, Q8L8Q7, Q8W3E8, Q93Z08, Q94KT8, Q94LR4, Q99571, Q9C6E4, Q9FE06, Q9FHM9

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	10
Benign	14

Top pathogenic / likely-pathogenic (0)

SpliceAI

444 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72136118:CAGG:C	donor_loss	1.0000
11:72136119:AGGT:A	donor_loss	1.0000
11:72136120:GG:G	donor_loss	1.0000
11:72136121:G:A	donor_loss	1.0000
11:72136122:T:A	donor_loss	1.0000
11:72138959:A:AG	acceptor_gain	1.0000
11:72138960:G:GT	acceptor_gain	1.0000
11:72138960:GT:G	acceptor_gain	1.0000
11:72138960:GTGC:G	acceptor_gain	1.0000
11:72138960:GTGCA:G	acceptor_gain	1.0000
11:72139341:A:AG	acceptor_gain	1.0000
11:72139342:C:G	acceptor_gain	1.0000
11:72139342:CTCA:C	acceptor_loss	1.0000
11:72139345:A:AG	acceptor_gain	1.0000
11:72139345:AG:A	acceptor_gain	1.0000
11:72139346:G:A	acceptor_gain	1.0000
11:72139346:G:GG	acceptor_gain	1.0000
11:72139346:GGT:G	acceptor_gain	1.0000
11:72139346:GGTC:G	acceptor_gain	1.0000
11:72139346:GGTCA:G	acceptor_gain	1.0000
11:72139480:CAGG:C	donor_loss	1.0000
11:72139481:AGG:A	donor_loss	1.0000
11:72139483:G:GG	donor_gain	1.0000
11:72139484:T:G	donor_loss	1.0000
11:72139496:GAGA:G	donor_gain	1.0000
11:72136103:G:GT	donor_gain	0.9900
11:72138956:CCCAG:C	acceptor_loss	0.9900
11:72138957:CCAGT:C	acceptor_loss	0.9900
11:72138958:CA:C	acceptor_loss	0.9900
11:72138959:A:C	acceptor_loss	0.9900

AlphaMissense

1646 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72138972:G:C	W60C	0.991
11:72138972:G:T	W60C	0.991
11:72139140:G:C	W116C	0.990
11:72139140:G:T	W116C	0.990
11:72139733:T:C	F214L	0.990
11:72139735:T:A	F214L	0.990
11:72139735:T:G	F214L	0.990
11:72139457:G:C	W156C	0.989
11:72139457:G:T	W156C	0.989
11:72139469:G:C	W160C	0.989
11:72139469:G:T	W160C	0.989
11:72139415:G:C	W142C	0.988
11:72139415:G:T	W142C	0.988
11:72139418:G:C	W143C	0.987
11:72139418:G:T	W143C	0.987
11:72139138:T:A	W116R	0.980
11:72139138:T:C	W116R	0.980
11:72138961:T:A	C57S	0.978
11:72138962:G:C	C57S	0.978
11:72139117:T:A	C109S	0.976
11:72139118:G:C	C109S	0.976
11:72138988:T:A	C66S	0.975
11:72138989:G:C	C66S	0.975
11:72139425:T:A	C146S	0.974
11:72139426:G:C	C146S	0.974
11:72139443:T:A	C152S	0.974
11:72139444:G:C	C152S	0.974
11:72139467:T:A	W160R	0.974
11:72139467:T:C	W160R	0.974
11:72139598:T:A	C169S	0.974

dbSNP variants (sampled 300 via entrez): RS1000335892 (11:72139655 CT>C), RS1001095575 (11:72135385 C>A), RS1001210108 (11:72134248 C>T), RS1001277731 (11:72135532 T>A,C), RS1001369035 (11:72139565 G>T), RS1001587689 (11:72139366 A>G), RS1001827807 (11:72134037 G>T), RS1001913589 (11:72138271 C>T), RS1003032877 (11:72138510 G>A), RS1003370013 (11:72137326 C>A,T), RS1004369130 (11:72140030 AG>A), RS1004374975 (11:72134283 A>G), RS1004809728 (11:72135688 G>A,T), RS1005609562 (11:72137589 T>G), RS1006360781 (11:72136210 G>A,T)

Disease associations

OMIM: gene MIM:602469 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs61734430	Efficacy	3	pemetrexed	Mesothelioma;Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs61734430	FOLR3	3	2.50	1	pemetrexed

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
sodium arsenate	increases abundance, increases expression	1
o,p’-DDT	increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	affects expression	1
jinfukang	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Coal	increases abundance, increases expression	1
Polychlorinated Biphenyls	affects expression	1
Silicon Dioxide	increases expression	1
Smoke	increases abundance, increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1

Clinical trials (associated diseases)

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