MTHFSD

Summary

MTHFSD (methenyltetrahydrofolate synthetase domain containing, HGNC:25778) is a protein-coding gene on chromosome 16q24.1, encoding Methenyltetrahydrofolate synthase domain-containing protein (Q2M296).

Enables RNA binding activity. Predicted to be active in cytoplasm.

Source: NCBI Gene 64779 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 89 total — 1 pathogenic
• MANE Select transcript: NM_001159377

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25778
Approved symbol	MTHFSD
Name	methenyltetrahydrofolate synthetase domain containing
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12998
Ensembl gene	ENSG00000103248
Ensembl biotype	protein_coding
OMIM	616820
Entrez	64779

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron, 1 TEC

ENST00000360900, ENST00000381214, ENST00000543303, ENST00000546093, ENST00000561522, ENST00000561848, ENST00000561989, ENST00000562096, ENST00000562940, ENST00000562994, ENST00000564364, ENST00000565482, ENST00000566050, ENST00000566469, ENST00000567539, ENST00000568037, ENST00000568798, ENST00000569000, ENST00000625049, ENST00000634347, ENST00000950129

RefSeq mRNA: 5 — MANE Select: NM_001159377 NM_001159377, NM_001159378, NM_001159379, NM_001159380, NM_022764

CCDS: CCDS42211, CCDS54047, CCDS54048, CCDS58490

Canonical transcript exons

ENST00000360900 — 8 exons

Exon	Start	End
ENSE00002235294	86530186	86532481
ENSE00003463333	86546559	86546649
ENSE00003469186	86555169	86555235
ENSE00003490121	86548464	86548577
ENSE00003495966	86541697	86541822
ENSE00003655316	86542101	86542213
ENSE00003655939	86552033	86552146
ENSE00003721184	86554645	86554751

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 93.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3623 / max 82.6070, expressed in 1774 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158446	8.3623	1774

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	93.18	gold quality
right uterine tube	UBERON:0001302	90.46	gold quality
minor salivary gland	UBERON:0001830	85.59	gold quality
granulocyte	CL:0000094	85.41	gold quality
left testis	UBERON:0004533	85.41	gold quality
rectum	UBERON:0001052	85.33	gold quality
right lobe of thyroid gland	UBERON:0001119	85.27	gold quality
right testis	UBERON:0004534	85.21	gold quality
gall bladder	UBERON:0002110	84.92	gold quality
left lobe of thyroid gland	UBERON:0001120	84.66	gold quality
skin of abdomen	UBERON:0001416	84.61	gold quality
skin of leg	UBERON:0001511	84.49	gold quality
body of pancreas	UBERON:0001150	84.35	gold quality
stromal cell of endometrium	CL:0002255	84.30	gold quality
apex of heart	UBERON:0002098	84.18	gold quality
metanephros cortex	UBERON:0010533	84.12	gold quality
right adrenal gland cortex	UBERON:0035827	84.12	gold quality
right adrenal gland	UBERON:0001233	84.09	gold quality
endocervix	UBERON:0000458	84.02	gold quality
testis	UBERON:0000473	84.01	gold quality
mucosa of stomach	UBERON:0001199	83.99	gold quality
thyroid gland	UBERON:0002046	83.89	gold quality
left ovary	UBERON:0002119	83.89	gold quality
body of stomach	UBERON:0001161	83.85	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.79	gold quality
ganglionic eminence	UBERON:0004023	83.67	gold quality
right ovary	UBERON:0002118	83.63	gold quality
monocyte	CL:0000576	83.61	gold quality
transverse colon	UBERON:0001157	83.61	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.29
E-MTAB-6058	no	42.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

72 targeting MTHFSD, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4328	99.57	71.06	4094

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mthfsd	ENSDARG00000062042
mus_musculus	Mthfsd	ENSMUSG00000031816
rattus_norvegicus	Mthfsd	ENSRNOG00000046443
drosophila_melanogaster	lost	FBGN0263594

Protein

Protein identifiers

Methenyltetrahydrofolate synthase domain-containing protein — Q2M296 (reviewed: Q2M296)

All UniProt accessions (14): Q2M296, A0A087WX22, F5H0M7, H3BML0, H3BMX6, H3BNE5, H3BP93, H3BPD2, H3BQU0, H3BSB5, H3BSD1, H3BSW8, H3BUU0, H3BVG2

Isoforms (4)

UniProt ID	Names	Canonical?
Q2M296-1	1	yes
Q2M296-2	2
Q2M296-3	3
Q2M296-4	4

RefSeq proteins (5): NP_001152849, NP_001152850, NP_001152851, NP_001152852, NP_073601 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR002698	FTHF_cligase	Family
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR024185	FTHF_cligase-like_sf	Homologous_superfamily
IPR034359	MTHFSD_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR037171	NagB/RpiA_transferase-like	Homologous_superfamily

Pfam: PF00076, PF01812

UniProt features (21 total): strand 6, sequence variant 5, sequence conflict 2, helix 2, splice variant 2, chain 1, domain 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2E5J	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2M296-F1	85.20	0.67

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 52 (showing top): EBNA1BP2_TARGET_GENES, FEV_TARGET_GENES, GLI3_TARGET_GENES, LMTK3_TARGET_GENES, NFKBIA_TARGET_GENES, ZNF436_TARGET_GENES, ZNF528_TARGET_GENES, ZNF92_TARGET_GENES, MIR3942_3P, MIR4447, MIR5196_5P, MIR4747_5P, MIR1253, MIR4472, MIR1912_3P

GO Biological Process (0):

GO Molecular Function (2): RNA binding (GO:0003723), nucleic acid binding (GO:0003676)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleic acid binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1690 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTHFSD	FOXL1	Q12952	633
MTHFSD	MTHFS	P49914	619
MTHFSD	FOXF1	Q12946	550
MTHFSD	TMEM200C	A6NKL6	547
MTHFSD	GPAT2	Q6NUI2	532
MTHFSD	SH2D4A	Q9H788	511
MTHFSD	DEF8	Q6ZN54	505
MTHFSD	ABLIM3	O94929	466
MTHFSD	MTFMT	Q96DP5	458
MTHFSD	FOXC2	Q99958	447
MTHFSD	SYCP2	Q9BX26	441
MTHFSD	DAGLB	Q8NCG7	438
MTHFSD	PDCD5	O14737	434
MTHFSD	TCF25	Q9BQ70	424
MTHFSD	ADAM22	Q9P0K1	417

IntAct

10 interactions, top by confidence:

A	B	Type	Score
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
EFCAB2	IQGAP2	psi-mi:“MI:0914”(association)	0.350
C1orf174	POLRMT	psi-mi:“MI:0914”(association)	0.350
H1-1	POLRMT	psi-mi:“MI:0914”(association)	0.350
MACROH2A2	ZNF316	psi-mi:“MI:0914”(association)	0.350
PYM1	POLRMT	psi-mi:“MI:0914”(association)	0.350
SERBP1	ZNF593	psi-mi:“MI:0914”(association)	0.350
ZNF346	ZNF316	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): MTHFSD (Affinity Capture-RNA), MTHFSD (Affinity Capture-MS), MTHFSD (Affinity Capture-MS), MTHFSD (Affinity Capture-MS), MTHFSD (Affinity Capture-MS), MTHFSD (Protein-RNA), MTHFSD (Cross-Linking-MS (XL-MS)), MTHFSD (Co-fractionation), MTHFSD (Co-fractionation), MTHFSD (Protein-peptide), MTHFSD (Affinity Capture-RNA), MTHFSD (Affinity Capture-Western), MTHFSD (Affinity Capture-Western), MTHFSD (Affinity Capture-Western), MTHFSD (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2MDK8, A7SLX5, A7YY46, D3ZEY4, D3ZX08, E9QAM5, O59713, O95822, P0C7A1, P48760, P52333, P52824, Q002B5, Q07071, Q14397, Q15477, Q2KI24, Q2M296, Q2NKY8, Q3SYT1, Q3T7C9, Q3U1Y4, Q3URQ7, Q4R380, Q52L34, Q567W6, Q568Y2, Q5I0I8, Q5NCQ5, Q5ZHX9, Q6GPQ5, Q6NZR5, Q6P5E8, Q8BUI3, Q8BX80, Q8C9A2, Q8NFF5, Q8NFI3, Q91X44, Q920F5

Diamond homologs: Q0P464, Q2KI24, Q2M296, Q3URQ7, Q52L34, Q9SRE0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	74
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
869495	NC_000016.9:g.86243180_87703229del	Pathogenic

SpliceAI

1947 predictions. Top by Δscore:

Variant	Effect	Δscore
16:86532482:C:CC	acceptor_gain	1.0000
16:86532482:CTG:C	acceptor_loss	1.0000
16:86541818:ACGAC:A	acceptor_gain	1.0000
16:86541819:CGAC:C	acceptor_gain	1.0000
16:86541819:CGACC:C	acceptor_gain	1.0000
16:86541820:GAC:G	acceptor_gain	1.0000
16:86541821:AC:A	acceptor_gain	1.0000
16:86541822:CC:C	acceptor_gain	1.0000
16:86541822:CCTGG:C	acceptor_loss	1.0000
16:86541823:C:CA	acceptor_loss	1.0000
16:86541823:C:CC	acceptor_gain	1.0000
16:86541824:T:A	acceptor_loss	1.0000
16:86542081:AG:A	donor_gain	1.0000
16:86542081:AGC:A	donor_gain	1.0000
16:86542081:AGCC:A	donor_gain	1.0000
16:86548573:TTGCT:T	acceptor_gain	1.0000
16:86548576:CT:C	acceptor_gain	1.0000
16:86548578:C:CC	acceptor_gain	1.0000
16:86548579:T:C	acceptor_gain	1.0000
16:86532477:CTGAT:C	acceptor_gain	0.9900
16:86532478:TGAT:T	acceptor_gain	0.9900
16:86541692:CCCA:C	donor_loss	0.9900
16:86541693:CCACC:C	donor_loss	0.9900
16:86541694:CACCT:C	donor_loss	0.9900
16:86541695:A:G	donor_loss	0.9900
16:86541823:C:T	acceptor_gain	0.9900
16:86542050:C:CA	donor_gain	0.9900
16:86542082:G:C	donor_gain	0.9900
16:86542096:AGCAC:A	donor_loss	0.9900
16:86542097:GCAC:G	donor_loss	0.9900

AlphaMissense

2475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:86548558:A:T	V86D	0.992
16:86546570:A:T	V144D	0.991
16:86554648:A:C	F40L	0.991
16:86554648:A:T	F40L	0.991
16:86554650:A:G	F40L	0.991
16:86542197:C:A	K153N	0.990
16:86542197:C:G	K153N	0.990
16:86542114:A:T	V181D	0.989
16:86542206:T:A	R150S	0.989
16:86542206:T:G	R150S	0.989
16:86554728:G:T	R14S	0.985
16:86546573:G:T	A143D	0.984
16:86546574:C:G	A143P	0.984
16:86552071:C:G	D67H	0.984
16:86546580:A:G	S141P	0.983
16:86554681:A:C	F29L	0.983
16:86554681:A:T	F29L	0.983
16:86554683:A:G	F29L	0.983
16:86554738:T:A	K10N	0.983
16:86554738:T:G	K10N	0.983
16:86542207:C:G	R150T	0.982
16:86542123:A:T	V178D	0.981
16:86548474:G:T	A114D	0.981
16:86546632:A:C	S123R	0.980
16:86546632:A:T	S123R	0.980
16:86546634:T:G	S123R	0.980
16:86552069:A:C	D67E	0.980
16:86552069:A:T	D67E	0.980
16:86552070:T:A	D67V	0.980
16:86554658:A:G	I37T	0.980

dbSNP variants (sampled 300 via entrez): RS1000030343 (16:86551937 C>G,T), RS1000361324 (16:86547308 T>G), RS1000388796 (16:86530345 C>G,T), RS1000417582 (16:86534949 T>C), RS1000566624 (16:86545718 C>A,T), RS1000616385 (16:86555275 C>A,T), RS1000740579 (16:86541766 G>A,C), RS1000761207 (16:86530563 C>T), RS1000874485 (16:86554368 G>A,C), RS1001086885 (16:86542821 C>G,T), RS1001282173 (16:86536878 A>T), RS1001296984 (16:86543098 T>C), RS1001336236 (16:86537046 T>C), RS1001352053 (16:86538146 G>A), RS1001411315 (16:86547765 G>A)

Disease associations

OMIM: gene MIM:616820 | disease phenotypes: MIM:265380

GenCC curated gene-disease

Mondo (1): alveolar capillary dysplasia with misalignment of pulmonary veins (MONDO:0009934)

Orphanet (1): Congenital alveolar capillary dysplasia (Orphanet:210122)

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004025_25	Systemic juvenile idiopathic arthritis	5.000000e-06
GCST006431_17	Plasma parathyroid hormone levels	2.000000e-06
GCST007431_55	Lung function (FEV1/FVC)	7.000000e-09
GCST007432_60	FEV1	4.000000e-10
GCST011365_151	Myocardial infarction	2.000000e-06
GCST011742_68	Triglyceride levels in HIV infection	7.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536590	Alveolar capillary dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
entinostat	decreases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
Sunitinib	increases expression	1
Benzo(a)pyrene	affects methylation	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Lead	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ribonucleotides	affects binding	1
Testosterone	decreases expression	1
Asbestos, Serpentine	decreases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00732537	PHASE4	COMPLETED	Inhaled Nitric Oxide by Oxygen Hood in Neonates
NCT04328636	PHASE1/PHASE2	COMPLETED	Nebulized MgSO4 in Persistent Pulmonary Hypertension of Newborn