DHFR2

Summary

DHFR2 (dihydrofolate reductase 2, HGNC:27309) is a protein-coding gene on chromosome 3q11.2, encoding Dihydrofolate reductase 2, mitochondrial (Q86XF0). Key enzyme in folate metabolism. It is a selective cancer dependency (DepMap: 33.9% of cell lines).

Enables dihydrofolate reductase activity and mRNA binding activity. Involved in tetrahydrofolate metabolic process and thymidine biosynthetic process. Located in mitochondrial inner membrane and mitochondrial matrix.

Source: NCBI Gene 200895 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 9 total
• Cancer dependency (DepMap): dependent in 33.9% of screened cell lines
• MANE Select transcript: NM_176815

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27309
Approved symbol	DHFR2
Name	dihydrofolate reductase 2
Location	3q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ16119
Ensembl gene	ENSG00000178700
Ensembl biotype	protein_coding
OMIM	616588
Entrez	200895

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000314636, ENST00000394221, ENST00000461173, ENST00000481631, ENST00000496983, ENST00000619045, ENST00000951344

RefSeq mRNA: 2 — MANE Select: NM_176815 NM_001195643, NM_176815

CCDS: CCDS2926

Canonical transcript exons

ENST00000314636 — 2 exons

Exon	Start	End
ENSE00001517776	94057922	94061606
ENSE00001915781	94062746	94062916

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 98.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.7208 / max 35.7857, expressed in 1635 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43310	3.6613	1517
43309	1.0595	733

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.94	gold quality
pancreatic ductal cell	CL:0002079	95.57	silver quality
kidney epithelium	UBERON:0004819	91.11	silver quality
inferior vagus X ganglion	UBERON:0005363	90.09	gold quality
renal medulla	UBERON:0000362	89.21	gold quality
lateral globus pallidus	UBERON:0002476	88.91	gold quality
ventral tegmental area	UBERON:0002691	88.62	gold quality
subthalamic nucleus	UBERON:0001906	88.38	gold quality
ileal mucosa	UBERON:0000331	88.22	gold quality
epithelial cell of pancreas	CL:0000083	87.89	gold quality
endothelial cell	CL:0000115	87.66	gold quality
thymus	UBERON:0002370	87.59	gold quality
layer of synovial tissue	UBERON:0007616	87.44	gold quality
dorsal plus ventral thalamus	UBERON:0001897	87.40	gold quality
medulla oblongata	UBERON:0001896	87.14	gold quality
trigeminal ganglion	UBERON:0001675	86.96	gold quality
pylorus	UBERON:0001166	86.72	gold quality
superior surface of tongue	UBERON:0007371	86.62	gold quality
nipple	UBERON:0002030	86.32	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.19	gold quality
superior vestibular nucleus	UBERON:0007227	85.89	gold quality
substantia nigra pars compacta	UBERON:0001965	85.73	gold quality
globus pallidus	UBERON:0001875	85.60	gold quality
cardia of stomach	UBERON:0001162	85.35	gold quality
sperm	CL:0000019	85.24	silver quality
lateral nuclear group of thalamus	UBERON:0002736	85.07	gold quality
trachea	UBERON:0003126	84.93	gold quality
calcaneal tendon	UBERON:0003701	84.85	gold quality
upper arm skin	UBERON:0004263	84.81	silver quality
medial globus pallidus	UBERON:0002477	84.76	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.57
E-ENAD-21	no	17.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

71 targeting DHFR2, 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-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-520A-5P	99.35	66.72	1632

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 33.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• The results of this study suggest that genetic variants of methionine metabolism are associated with meningioma formation (PMID:18447718)
• The DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. (PMID:21876184)
• We hope this work will be useful to understand the general characteristics of DHFRL1. (PMID:24122410)
• A dihydrofolate reductase 2 (DHFR2) variant is associated with risk of neural tube defects in an Irish cohort but not in a United Kingdom cohort. (PMID:33544972)
• The Differential Translation Capabilities of the Human DHFR2 Gene Indicates a Developmental and Tissue-Specific Endogenous Protein of Low Abundance. (PMID:38224738)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhfr	ENSDARG00000004251
danio_rerio	zgc:153031	ENSDARG00000068876
mus_musculus	Dhfr	ENSMUSG00000021707
rattus_norvegicus		ENSRNOG00000082925
drosophila_melanogaster	Dhfr	FBGN0004087
caenorhabditis_elegans	dhfr-1	WBGENE00007974

Paralogs (2): TYMS (ENSG00000176890), DHFR (ENSG00000228716)

Protein

Protein identifiers

Dihydrofolate reductase 2, mitochondrial — Q86XF0 (reviewed: Q86XF0)

Alternative names: Dihydrofolate reductase, mitochondrial, Dihydrofolate reductase-like protein 1

All UniProt accessions (2): C9JJ68, Q86XF0

UniProt curated annotations — full annotation on UniProt →

Function. Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Binds its own mRNA and that of DHFR.

Subcellular location. Mitochondrion. Mitochondrion matrix. Mitochondrion inner membrane.

Tissue specificity. Expressed in numerous cell lines.

Pathway. Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate: step 1/1.

Miscellaneous. Humans have acquired two dihydrofolate reductase enzymes during their evolution, DHFR and DHFR2. In contrast to human, mice and brown rats have just one.

Similarity. Belongs to the dihydrofolate reductase family.

RefSeq proteins (2): NP_001182572, NP_789785* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001796	DHFR_dom	Domain
IPR012259	DHFR	Family
IPR024072	DHFR-like_dom_sf	Homologous_superfamily

Pfam: PF00186

Enzyme classification (BRENDA):

• EC 1.5.1.3 — dihydrofolate reductase (BRENDA: 90 organisms, 121 substrates, 914 inhibitors, 438 Km, 293 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
7,8-DIHYDROFOLATE	—	241
NADPH	0.0004–0.415	157
DIHYDROFOLATE	0.0006–0.238	8
8-METHYLPTERIN	0.03–0.3	4
FOLATE	0.0041–0.0067	2
NADH	0.268–0.32	2
10-FORMYL-DIHYDROFOLATE	0.003	1
6-HYDROXYMETHYLPTERIN	0.0034	1
DIHYDROPTEROATE	0.0009	1
L-THREO-NEOPTERIN	0.0035	1
NADP+	0.123	1
ACETYLPYRIDINE ADENINE NUCLEOTIDE	—	0

Catalyzed reactions (Rhea), 1 shown:

• (6S)-5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate + NADPH + H(+) (RHEA:15009)

UniProt features (10 total): binding site 7, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XF0-F1	96.06	0.96

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 (7): 10; 16–22; 31–36; 55–57; 71; 77–79; 117–124

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines

MSigDB gene sets: 77 (showing top): GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_FOLIC_ACID_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, TGCTGAY_UNKNOWN, GOBP_TETRAHYDROFOLATE_METABOLIC_PROCESS, GOBP_ONE_CARBON_METABOLIC_PROCESS, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (6): one-carbon metabolic process (GO:0006730), thymidine biosynthetic process (GO:0046105), dihydrofolate metabolic process (GO:0046452), tetrahydrofolate metabolic process (GO:0046653), tetrahydrofolate biosynthetic process (GO:0046654), folic acid metabolic process (GO:0046655)

GO Molecular Function (6): mRNA binding (GO:0003729), dihydrofolate reductase activity (GO:0004146), folate reductase activity (GO:0033560), NADP binding (GO:0050661), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
folic acid-containing compound metabolic process	3
dicarboxylic acid metabolic process	2
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	2
cytoplasm	2
cellular anatomical structure	2
small molecule metabolic process	1
thymidine metabolic process	1
pyrimidine deoxyribonucleoside biosynthetic process	1
folic acid-containing compound biosynthetic process	1
tetrahydrofolate metabolic process	1
RNA binding	1
adenyl nucleotide binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHFR2	TYMS	P04818	998
DHFR2	DHODH	Q02127	908
DHFR2	GART	P22102	881
DHFR2	SPR	P35270	849
DHFR2	TK2	O00142	842
DHFR2	SHMT1	P34896	815
DHFR2	MTHFD1	P11586	809
DHFR2	QDPR	P09417	803
DHFR2	CBR1	P16152	802
DHFR2	MTHFR	P42898	794
DHFR2	TCN2	P20062	791
DHFR2	HSPD1	P10809	790
DHFR2	FPGS	Q05932	790
DHFR2	ATIC	P31939	735
DHFR2	GCH1	P30793	722

IntAct

73 interactions, top by confidence:

A	B	Type	Score
DHFR	DHFR2	psi-mi:“MI:0915”(physical association)	0.560
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
SERPINA6	COCH	psi-mi:“MI:0914”(association)	0.530
BRINP3	BUB1	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
LIPH	LRP5	psi-mi:“MI:0914”(association)	0.530
ADAM33	LRP5	psi-mi:“MI:0914”(association)	0.530
GAA	B3GAT3	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
ADAM21	PLXNA2	psi-mi:“MI:0914”(association)	0.530
CBLN4	C1QL1	psi-mi:“MI:0914”(association)	0.530
TINF2	DHFR2	psi-mi:“MI:0915”(physical association)	0.370
PCDHA12	KLRG2	psi-mi:“MI:0914”(association)	0.350
SERPINA7	RTL8C	psi-mi:“MI:0914”(association)	0.350
PLAUR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
OLFM4	DDX11L8	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B		psi-mi:“MI:0914”(association)	0.350
PCDH20		psi-mi:“MI:0914”(association)	0.350
GML	CLSTN1	psi-mi:“MI:0914”(association)	0.350
TMEM25	FUZ	psi-mi:“MI:0914”(association)	0.350
MPPE1	ADAM10	psi-mi:“MI:0914”(association)	0.350
PTCH1	PLXNB2	psi-mi:“MI:0914”(association)	0.350
ADAM21	PLXNB2	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350
IDS	COCH	psi-mi:“MI:0914”(association)	0.350
CBLN4	ADAM11	psi-mi:“MI:0914”(association)	0.350

BioGRID (324): DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1J6KGJ9, A0A314KSQ4, B0BNF8, B4G0F3, B8BKI7, B9N1F9, B9SQI7, C6JS30, E0CSI1, O80526, O82782, P00374, P00375, P00376, P00377, P00378, P04753, P09503, P11172, P27421, P29411, Q05B63, Q28DS0, Q2QNG7, Q2R483, Q5I0K3, Q5NVE1, Q5R421, Q5R514, Q5R8R4, Q5R962, Q5RDZ0, Q5RFI8, Q5ZID6, Q640V9, Q69YN2, Q6YJI5, Q7SYN4, Q7TNK6, Q7Z4G4

Diamond homologs: G4VJD6, O02604, O62583, O81395, P00374, P00375, P00376, P00377, P00378, P04174, P04753, P07382, P07807, P09503, P0A547, P0ABQ4, P0ABQ5, P0ABQ6, P0C0P0, P0C0P1, P11045, P12833, P13922, P13955, P16126, P16184, P17719, P20712, P22573, P22906, P27421, P28019, P31073, P31074, P36591, P43791, P45350, P46103, P51820, P57243

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DHFR2	“down-regulates quantity”	dihydrofolate(2-)	“chemical modification”
DHFR2	“up-regulates quantity”	(6S)-5,6,7,8-tetrahydrofolate(2-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

772 predictions. Top by Δscore:

Variant	Effect	Δscore
3:94049404:A:AG	acceptor_gain	1.0000
3:94049405:G:GG	acceptor_gain	1.0000
3:94053185:A:AG	acceptor_gain	1.0000
3:94053186:G:GG	acceptor_gain	1.0000
3:94063041:G:GT	donor_gain	1.0000
3:94063139:GTGA:G	donor_loss	1.0000
3:94063140:T:G	donor_loss	1.0000
3:94049402:GTA:G	acceptor_loss	0.9900
3:94049403:TAGCT:T	acceptor_loss	0.9900
3:94049404:AG:A	acceptor_loss	0.9900
3:94049405:G:GC	acceptor_loss	0.9900
3:94049405:GCTA:G	acceptor_gain	0.9900
3:94050822:A:AG	acceptor_gain	0.9900
3:94050823:G:GG	acceptor_gain	0.9900
3:94051402:C:CG	donor_gain	0.9900
3:94053186:GA:G	acceptor_gain	0.9900
3:94053186:GAT:G	acceptor_gain	0.9900
3:94053186:GATT:G	acceptor_gain	0.9900
3:94053186:GATTT:G	acceptor_gain	0.9900
3:94063139:G:GG	donor_gain	0.9900
3:94049405:GCT:G	acceptor_gain	0.9800
3:94049405:GCTAA:G	acceptor_gain	0.9800
3:94049519:CCTGG:C	donor_loss	0.9800
3:94049523:G:GC	donor_loss	0.9800
3:94049524:TGA:T	donor_loss	0.9800
3:94049525:G:GT	donor_loss	0.9800
3:94049526:AGTA:A	donor_loss	0.9800
3:94049527:G:C	donor_loss	0.9800
3:94050822:AGTT:A	acceptor_gain	0.9800
3:94050823:GTT:G	acceptor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000038209 (3:94065212 C>G,T), RS1000070825 (3:94064771 C>A,G,T), RS1000535919 (3:94063407 C>T), RS1001042793 (3:94063680 C>G,T), RS1001075510 (3:94063396 C>T), RS1001646443 (3:94060031 G>C), RS1001786376 (3:94060200 G>A), RS1002414051 (3:94064284 C>A), RS1003862194 (3:94061783 C>G), RS1004150727 (3:94061295 T>A,C), RS1005107135 (3:94059530 T>C), RS1005609271 (3:94062715 C>A), RS1005772679 (3:94062519 G>C), RS1006080354 (3:94062883 A>C), RS1006886237 (3:94063279 C>T)

Disease associations

OMIM: gene MIM:616588 | disease phenotypes: MIM:612291

GenCC curated gene-disease

Mondo (1): Joubert syndrome 8 (MONDO:0012855)

Orphanet (1): Isolated Joubert syndrome (Orphanet:475)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005830_118	Hand grip strength	2.000000e-10
GCST009391_1008	Metabolite levels	5.000000e-06
GCST009391_2027	Metabolite levels	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006941	grip strength measurement
EFO:0010359	lysophosphatidylcholine 18:0 measurement
EFO:0010371	lysophosphatidylethanolamine 22:6 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567358	Joubert Syndrome 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
sodium arsenite	increases abundance, increases expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC668394	decreases expression	1
Irinotecan	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Arsenic	increases abundance, increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Oxyquinoline	decreases expression	1
Gold Compounds	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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