MTHFD1L

Summary

MTHFD1L (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like, HGNC:21055) is a protein-coding gene on chromosome 6q25.1, encoding Monofunctional C1-tetrahydrofolate synthase, mitochondrial (Q6UB35). May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism complementing thus the enzymatic activities of MTHFD2.

The protein encoded by this gene is involved in the synthesis of tetrahydrofolate (THF) in the mitochondrion. THF is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 25902 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 173 total
• Druggable target: yes
• MANE Select transcript: NM_015440

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21055
Approved symbol	MTHFD1L
Name	methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like
Location	6q25.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP586G1517, FLJ21145
Ensembl gene	ENSG00000120254
Ensembl biotype	protein_coding
OMIM	611427
Entrez	25902

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000367307, ENST00000367308, ENST00000367321, ENST00000420192, ENST00000421497, ENST00000423867, ENST00000441122, ENST00000450635, ENST00000453602, ENST00000478643, ENST00000611279, ENST00000618312, ENST00000939695, ENST00000968101

RefSeq mRNA: 11 — MANE Select: NM_015440 NM_001242767, NM_001242768, NM_001242769, NM_001350486, NM_001350487, NM_001350488, NM_001350489, NM_001350491, NM_001350492, NM_001350493, NM_015440

CCDS: CCDS5228, CCDS56457, CCDS75535, CCDS75536

Canonical transcript exons

ENST00000367321 — 28 exons

Exon	Start	End
ENSE00001903601	150865702	150866049
ENSE00001933014	151101526	151101887
ENSE00002174698	150887845	150887981
ENSE00002214706	151034493	151034600
ENSE00002227551	151013779	151013820
ENSE00002234018	150945467	150945541
ENSE00002236105	150960275	150960415
ENSE00002236964	150964969	150965037
ENSE00002242938	150944486	150944593
ENSE00002245332	151015516	151015693
ENSE00002255601	150936804	150936940
ENSE00002256488	150949031	150949133
ENSE00002267522	151092467	151092587
ENSE00002270253	150938699	150938745
ENSE00002287764	150971947	150972058
ENSE00002289410	151014880	151014980
ENSE00002318338	150955995	150956071
ENSE00002468596	151036965	151037117
ENSE00003561103	150918577	150918668
ENSE00003589795	150877634	150877684
ENSE00003637286	150876090	150876174
ENSE00003639198	150922205	150922302
ENSE00003668615	151009819	151009958
ENSE00003674551	150905650	150905761
ENSE00003719030	150926122	150926295
ENSE00003721339	150877773	150877826
ENSE00003726717	150885634	150885734
ENSE00003732753	150882762	150882886

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 96.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.2409 / max 193.4254, expressed in 1764 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70557	15.9206	1749
70562	1.8094	968
70558	1.0810	746
70559	1.0536	664
70560	0.1880	74
70569	0.0571	16
70556	0.0525	14
70561	0.0497	12
204252	0.0290	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	96.77	gold quality
stromal cell of endometrium	CL:0002255	95.68	gold quality
left coronary artery	UBERON:0001626	94.89	gold quality
coronary artery	UBERON:0001621	94.29	gold quality
cartilage tissue	UBERON:0002418	92.08	gold quality
ascending aorta	UBERON:0001496	91.43	gold quality
thoracic aorta	UBERON:0001515	91.32	gold quality
endothelial cell	CL:0000115	90.52	gold quality
aorta	UBERON:0000947	90.26	gold quality
tibia	UBERON:0000979	90.14	gold quality
popliteal artery	UBERON:0002250	89.64	gold quality
tibial artery	UBERON:0007610	89.64	gold quality
cerebellar hemisphere	UBERON:0002245	88.06	gold quality
cerebellar cortex	UBERON:0002129	87.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.54	gold quality
cerebellum	UBERON:0002037	87.50	gold quality
sural nerve	UBERON:0015488	87.02	gold quality
descending thoracic aorta	UBERON:0002345	86.90	gold quality
adrenal tissue	UBERON:0018303	86.64	gold quality
germinal epithelium of ovary	UBERON:0001304	86.38	gold quality
saphenous vein	UBERON:0007318	86.37	gold quality
epithelial cell of pancreas	CL:0000083	86.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.30	gold quality
decidua	UBERON:0002450	86.00	gold quality
cortical plate	UBERON:0005343	85.48	gold quality
ventricular zone	UBERON:0003053	85.19	gold quality
amniotic fluid	UBERON:0000173	85.18	gold quality
islet of Langerhans	UBERON:0000006	85.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.05	gold quality
upper lobe of left lung	UBERON:0008952	84.32	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

21 targeting MTHFD1L, 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-9-5P	100.00	72.28	2361
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-509-3-5P	97.21	67.74	1517
HSA-MIR-509-5P	97.21	67.90	1512
HSA-MIR-4418	97.04	67.16	1372
HSA-MIR-4693-3P	95.23	65.92	735

Literature-anchored findings (GeneRIF, showing 20)

• mitochondrial C1-tetrahydrofolate synthase gene structure and tissue distribution (PMID:12937168)
• Overexpression of C1-tetrahydrofolate synthase in fetal Down syndrome brain at the early second trimester may indicate abnormal folate metabolism and may reflect folate deficiency. (PMID:15068241)
• Gene encodes the mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase, a monofunctional enzyme containing formyl-THF synthetase activity. (PMID:16171773)
• association of rs6922269 with coronary heart disease not replicated in Tunisian sample (PMID:19373437)
• Two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts. (PMID:19777576)
• No evidence of association between the MTHFD1L marker and susceptibility to Alzheimer’s disease is found in a sample from a Spanish population. (PMID:21383495)
• Prevalence of minor allele A (adenosine) in rs11754661 single nucleotide polymorphism of MTHFD1L contributes to the risk of Alzheimer’s disease in a Han population of mainland China. (PMID:21741665)
• Strong candidate gene for mitochondrial disease, based on recessive mutations detected in infantile patients (PMID:22277967)
• This study support a role of MTHFD1L gene in late-onset Alzheimer’s disease in a Northern Han Chinese population. (PMID:22330827)
• The rs3832406 polymorphism was associated with isolated cleft lip with or without cleft palate.(MTHFD1L) (PMID:22520921)
• Results indicate that miR-9 and MiR-197 specifically downregulate MTHFD1L in HEK293 and MCF-7 cells and that SNPrs7646 affects miR-197 binding to the MTHFD1L 3’ UTR causing gene repression in the presence of the allele associated with neural tube defects. (PMID:24123340)
• MTHFD1L rs6922269 genotype is associated with active vitamin B12 levels at baseline and may be a marker of prognostic risk in patients with established coronary heart disease. (PMID:24618918)
• rs6922269 variant at MTHFD1L gene could be an important prognostic factor for cardiovascular mortality in patients after ACS. (PMID:25809277)
• Studies reported that the A allele of a polymorphism in a gene involved in folate metabolism, MTHFD1L, showed a genome-wide significant association with late-onset Alzheimer’s Disease. (PMID:26926881)
• study identifies MTHFD1L in the folate cycle as an important metabolic pathway in cancer cells with the potential for therapeutic targeting (PMID:28394261)
• MTHFD1L protein and RNA expression levels were significantly upregulated in esophageal squamous cell carcinoma tissue as compared with normal tissue. High expression of MTHFD1 was also detected in two esophageal cancer cell lines (TE-1 and EC109). (PMID:29171320)
• Results together with the limitations of the original studies indicate that the reported associations between the MTHFD1L and FOPNL loci and MM survival are false positives due to a winner’s curse effect. (PMID:31363079)
• MTHFD1L as a folate cycle enzyme correlates with prognostic outcome and its knockdown impairs cell invasive behaviors in osteosarcoma via mediating the AKT/mTOR pathway. (PMID:32456526)
• Integrative analysis reveals methylenetetrahydrofolate dehydrogenase 1-like as an independent shared diagnostic and prognostic biomarker in five different human cancers. (PMID:34908119)
• Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma. (PMID:35459186)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mthfd1l	ENSDARG00000042221
mus_musculus	Mthfd1l	ENSMUSG00000040675
rattus_norvegicus	Mthfd1l	ENSRNOG00000019582

Paralogs (3): MTHFD2 (ENSG00000065911), MTHFD1 (ENSG00000100714), MTHFD2L (ENSG00000163738)

Protein

Protein identifiers

Monofunctional C1-tetrahydrofolate synthase, mitochondrial — Q6UB35 (reviewed: Q6UB35)

Alternative names: Formyltetrahydrofolate synthetase

All UniProt accessions (9): A0A087WVM4, B7ZM99, Q6UB35, H0Y327, Q4VXM0, Q4VXM1, Q4VXV2, Q5JYA3, Q5JYA8

UniProt curated annotations — full annotation on UniProt →

Function. May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism complementing thus the enzymatic activities of MTHFD2.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion.

Tissue specificity. Detected in most tissues, highest expression found in placenta, thymus and brain. Low expression is found in liver and skeletal muscle. Up-regulated in colon adenocarcinoma.

Domain organisation. This monofunctional enzyme consists of two major domains: an N-terminal inactive methylene-THF dehydrogenase and cyclohydrolase domain and an active larger formyl-THF synthetase C-terminal domain.

Pathway. One-carbon metabolism; tetrahydrofolate interconversion.

Miscellaneous. May participate in the progression of colorectal cancer by conferring growth advantage. Could be a new molecular target for cancer therapy.

Similarity. In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family. In the C-terminal section; belongs to the formate–tetrahydrofolate ligase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UB35-1	1	yes
Q6UB35-2	2

RefSeq proteins (11): NP_001229696, NP_001229697, NP_001229698, NP_001337415, NP_001337416, NP_001337417, NP_001337418, NP_001337420, NP_001337421, NP_001337422, NP_056255* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000559	Formate_THF_ligase	Family
IPR000672	THF_DH/CycHdrlase	Family
IPR020628	Formate_THF_ligase_CS	Conserved_site
IPR020630	THF_DH/CycHdrlase_cat_dom	Domain
IPR020631	THF_DH/CycHdrlase_NAD-bd_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR046346	Aminoacid_DH-like_N_sf	Homologous_superfamily

Pfam: PF00763, PF01268, PF02882

Enzyme classification (BRENDA):

• EC 6.3.4.3 — formate-tetrahydrofolate ligase (BRENDA: 73 organisms, 52 substrates, 32 inhibitors, 87 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

16 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.012–0.59	25
FORMATE	0.035–38	23
TETRAHYDROFOLATE	0.015–2.3	14
5,6,7,8-TETRAHYDROPTEROYLTRIGLUTAMATE	0.0003–0.025	4
ADP	0.032–0.13	3
(6R,S)-TETRAHYDROFOLATE	0.33	2
5,6,7,8-TETRAHYDROPTEROYLDIGLUTAMATE	0.0055–0.029	2
(6R,S)-5,6,7,8-TETRAHYDROFOLATE	0.33	1
(6R,S)-TETRAHYDROFOLATE MONOGLUTAMATE	0.5	1
(6R,S)-TETRAHYDROFOLATE PTEROYLPENTAGLUTAMATE	0.0036	1
(6R,S)-TETRAHYDROFOLATE PTEROYLTRIGLUTAMATE	0.016	1
5,6,7,8-TETRAHYDROPTEROYLPENTAGLUTAMATE	0.003	1
5,6,7,8-TETRAHYDROPTEROYLTETRAGLUTAMATE	0.0001	1
CARBAMOYL PHOSPHATE	11.9	1
N10-FORMYLTETRAHYDROFOLATE	10	1

Catalyzed reactions (Rhea), 1 shown:

• (6S)-5,6,7,8-tetrahydrofolate + formate + ATP = (6R)-10-formyltetrahydrofolate + ADP + phosphate (RHEA:20221)

UniProt features (17 total): modified residue 4, region of interest 3, splice variant 2, sequence conflict 2, compositionally biased region 2, transit peptide 1, chain 1, sequence variant 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UB35-F1	87.45	0.73

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 (1): 423–430

Post-translational modifications (4): 357, 596, 189, 189

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines
R-HSA-1430728	Metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors

MSigDB gene sets: 216 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (12): neural tube closure (GO:0001843), folic acid-containing compound metabolic process (GO:0006760), 10-formyltetrahydrofolate biosynthetic process (GO:0009257), formate metabolic process (GO:0015942), formate biosynthetic process (GO:0015943), tetrahydrofolate interconversion (GO:0035999), embryonic neurocranium morphogenesis (GO:0048702), embryonic viscerocranium morphogenesis (GO:0048703), one-carbon metabolic process (GO:0006730), small molecule metabolic process (GO:0044281), carboxylic acid biosynthetic process (GO:0046394), tetrahydrofolate metabolic process (GO:0046653)

GO Molecular Function (6): formate-tetrahydrofolate ligase activity (GO:0004329), methylenetetrahydrofolate dehydrogenase (NADP+) activity (GO:0004488), ATP binding (GO:0005524), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), ligase activity (GO:0016874)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
embryonic morphogenesis	2
embryonic cranial skeleton morphogenesis	2
cytoplasm	2
cellular anatomical structure	2
primary neural tube formation	1
tube closure	1
modified amino acid metabolic process	1
pteridine-containing compound metabolic process	1
10-formyltetrahydrofolate metabolic process	1
dicarboxylic acid biosynthetic process	1
tetrahydrofolate biosynthetic process	1
monocarboxylic acid metabolic process	1
formate metabolic process	1
monocarboxylic acid biosynthetic process	1
one-carbon metabolic process	1
tetrahydrofolate metabolic process	1
small molecule metabolic process	1
metabolic process	1
carboxylic acid metabolic process	1
small molecule biosynthetic process	1
folic acid-containing compound metabolic process	1
ligase activity, forming carbon-nitrogen bonds	1
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2472 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTHFD1L	SHMT1	P34896	839
MTHFD1L	GLDC	P23378	810
MTHFD1L	SHMT2	P34897	790
MTHFD1L	ATIC	P31939	766
MTHFD1L	MTHFR	P42898	708
MTHFD1L	MTHFD2	P13995	690
MTHFD1L	FPGS	Q05932	689
MTHFD1L	PHGDH	O43175	689
MTHFD1L	MTHFD2L	Q9H903	677
MTHFD1L	SLC25A32	Q9H2D1	676
MTHFD1L	PSAT1	Q9Y617	667
MTHFD1L	PSPH	P78330	667
MTHFD1L	ALDH1L2	Q3SY69	664
MTHFD1L	TYMS	P04818	644
MTHFD1L	MTR	Q99707	644
MTHFD1L	GART	P22102	644

IntAct

95 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
MARS2	CLUH	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
AIFM1	HAX1	psi-mi:“MI:0914”(association)	0.420
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
Ncaph	ATP5MF-PTCD1	psi-mi:“MI:0914”(association)	0.350
LRPPRC	HSPA8	psi-mi:“MI:0914”(association)	0.350
NPM1	RPSA	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
TK	AP3B1	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
NS1		psi-mi:“MI:0914”(association)	0.350
NS1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
PB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
CEBPD	EEF1D	psi-mi:“MI:0914”(association)	0.350
NT5C3A	VWA8	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	NAP1L4	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
PTPMT1	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
NDUFA4	COX7A2L	psi-mi:“MI:0914”(association)	0.350

BioGRID (191): MTHFD1L (Co-fractionation), MTHFD1L (Co-fractionation), MTHFD1L (Co-fractionation), MTHFD1L (Co-fractionation), MTHFD1L (Co-fractionation), PAPOLA (Co-fractionation), PAPOLB (Co-fractionation), XPNPEP1 (Co-fractionation), MTHFD1L (Affinity Capture-MS), MTHFD1L (Proximity Label-MS), MTHFD1L (Affinity Capture-MS), MTHFD1L (Affinity Capture-MS), MTHFD1L (Affinity Capture-MS), MTHFD1L (Affinity Capture-MS), MTHFD1L (Two-hybrid)

ESM2 similar proteins: A0A067XGX8, A0A067XH53, A0A1D5AG16, A0MH68, B4GH42, B4Q9T2, B5E0H4, C8VJQ1, D8WUA4, I1R9A6, I1S489, P21357, P23225, P24493, P27608, P29976, P37215, P37216, P37822, Q00218, Q00681, Q01H90, Q03460, Q0DG35, Q0VCR7, Q1EHT7, Q3V3R1, Q42836, Q43155, Q43827, Q44524, Q5B7V0, Q69RJ0, Q6FLD4, Q6UB35, Q75LR2, Q75W16, Q7XUR2, Q8TGA2, Q8VYA1

Diamond homologs: A0KIN9, A0KSN0, A1B1M8, A1JMA3, A1RFN3, A1SAE2, A2RGS2, A3CL27, A3CZY6, A3DI22, A3PM52, A3QA17, A4FL80, A4J0S6, A4SPE5, A4WQ11, A4YAP3, A5G276, A5UPV2, A6WSY9, A7N5E9, A7NGQ9, A8F7D5, A8FQV1, A8H8Z4, A8MIN1, A9B4H8, A9IM41, A9KNJ5, A9L3Z6, A9WIW3, B0K5A5, B0KC36, B0TBP1, B0TVP3, B0UQF5, B1KJC0, B1ZJ88, B2IC30, B4ET09

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MTHFD1L	“up-regulates quantity”	formate	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	5	17.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	128
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

5804 predictions. Top by Δscore:

Variant	Effect	Δscore
6:150876088:A:AG	acceptor_gain	1.0000
6:150876089:G:GG	acceptor_gain	1.0000
6:150876089:GA:G	acceptor_gain	1.0000
6:150876089:GAGAA:G	acceptor_gain	1.0000
6:150876173:AGG:A	donor_loss	1.0000
6:150876174:GGTAA:G	donor_loss	1.0000
6:150876175:GTAAG:G	donor_loss	1.0000
6:150876176:T:G	donor_loss	1.0000
6:150877681:GGAG:G	donor_gain	1.0000
6:150877682:GAGG:G	donor_gain	1.0000
6:150877683:AGGTG:A	donor_loss	1.0000
6:150877684:GGTG:G	donor_loss	1.0000
6:150877685:G:A	donor_loss	1.0000
6:150882748:T:A	acceptor_gain	1.0000
6:150882760:A:AG	acceptor_gain	1.0000
6:150882761:G:GG	acceptor_gain	1.0000
6:150882761:GA:G	acceptor_gain	1.0000
6:150882761:GAT:G	acceptor_gain	1.0000
6:150882761:GATT:G	acceptor_gain	1.0000
6:150882761:GATTA:G	acceptor_gain	1.0000
6:150882882:GATGG:G	donor_gain	1.0000
6:150882884:TGG:T	donor_gain	1.0000
6:150882885:GG:G	donor_gain	1.0000
6:150882885:GGG:G	donor_gain	1.0000
6:150882886:GG:G	donor_gain	1.0000
6:150882886:GGTAA:G	donor_loss	1.0000
6:150882887:G:GA	donor_loss	1.0000
6:150882887:G:GG	donor_gain	1.0000
6:150882888:T:G	donor_loss	1.0000
6:150885626:T:TA	acceptor_gain	1.0000

AlphaMissense

6368 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:150936905:G:T	R453M	1.000
6:150936919:G:A	G458R	1.000
6:150936919:G:C	G458R	1.000
6:150936940:G:A	G465R	1.000
6:150936940:G:C	G465R	1.000
6:150971977:T:C	F682L	1.000
6:150971978:T:G	F682C	1.000
6:150971979:T:A	F682L	1.000
6:150971979:T:G	F682L	1.000
6:150971985:C:A	N684K	1.000
6:150971985:C:G	N684K	1.000
6:151009833:T:C	F714L	1.000
6:151009835:T:A	F714L	1.000
6:151009835:T:G	F714L	1.000
6:150936835:A:C	S430R	0.999
6:150936837:C:A	S430R	0.999
6:150936837:C:G	S430R	0.999
6:150936905:G:C	R453T	0.999
6:150936906:G:C	R453S	0.999
6:150936906:G:T	R453S	0.999
6:150936920:G:A	G458E	0.999
6:150936926:C:A	T460K	0.999
6:150936928:T:C	F461L	0.999
6:150936930:T:A	F461L	0.999
6:150936930:T:G	F461L	0.999
6:150936932:G:A	G462E	0.999
6:150936938:A:T	K464I	0.999
6:150936939:A:C	K464N	0.999
6:150936939:A:T	K464N	0.999
6:150938699:G:A	G465E	0.999

dbSNP variants (sampled 300 via entrez): RS1000021304 (6:150975512 A>G), RS1000053936 (6:151054533 G>A), RS1000062932 (6:151014121 C>T), RS1000104241 (6:151053107 A>T), RS1000107705 (6:150973390 G>A), RS1000119846 (6:151075629 C>T), RS1000122288 (6:150905516 C>T), RS1000130020 (6:150892943 G>A), RS1000132590 (6:150910436 G>T), RS1000146840 (6:151030128 G>A,T), RS1000162290 (6:150914120 A>G,T), RS1000195846 (6:150891639 C>T), RS1000221391 (6:150896046 G>A), RS1000223515 (6:150874196 A>G), RS1000225064 (6:150951538 A>G)

Disease associations

OMIM: gene MIM:611427 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000057_3	Coronary heart disease	3.000000e-08
GCST000808_4	Alzheimer’s disease (late onset)	2.000000e-10
GCST001063_1	Chronic myeloid leukemia	2.000000e-06
GCST002806_8	Type 2 diabetes	2.000000e-07
GCST004482_26	Peripheral arterial disease (traffic-related air pollution interaction)	8.000000e-08
GCST010002_338	Refractive error	5.000000e-20
GCST010396_264	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-07
GCST012490_576	Femur bone mineral density x serum urate levels interaction	4.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007908	traffic air pollution measurement
EFO:0007874	gut microbiome measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295869 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.65	Kd	2240	nM	CHEMBL5563248
5.43	Kd	3680	nM	CHEMBL5565291

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 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,3S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-phenylpropanoyl]amino]-3-methylpentanamide	2097934: Binding affinity to FTHFS (unknown origin) expressed in Escherichia coli BL21 (DE3) using IPTG as substrate assessed as dissociation constant by MST assay	kd	2.2400	uM
(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]-3-methylpentanamide	2097934: Binding affinity to FTHFS (unknown origin) expressed in Escherichia coli BL21 (DE3) using IPTG as substrate assessed as dissociation constant by MST assay	kd	3.6800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	6
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
bisphenol A	affects expression, affects cotreatment, decreases methylation, decreases expression	4
Estradiol	increases expression, increases reaction, affects expression	4
Valproic Acid	affects expression, decreases expression, increases methylation	4
trichostatin A	affects cotreatment, increases expression	3
Acetaminophen	decreases expression, increases expression	3
Cisplatin	affects expression, decreases expression	3
Cyclosporine	increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Nickel	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression	2
Tunicamycin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
OTX015	decreases expression	1
bisphenol F	increases expression	1
sodium arsenate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	affects methylation	1
1-nitropyrene	increases expression	1
pentabromodiphenyl ether	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118764	Binding	Binding affinity to MTHFD1L in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3BE	Abcam HEK293T MTHFD1L KO	Transformed cell line	Female
CVCL_SZ20	HAP1 MTHFD1L (-) 1	Cancer cell line	Male
CVCL_XQ74	HAP1 MTHFD1L (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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