Methotrexate toxicity

Summary

Methotrexate toxicity (MONDO:0034212) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 22
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3	Europe	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001410	Decreased liver function	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000155	Oral ulcer	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0001733	Pancreatitis	Occasional (5-29%)
HP:0001882	Leukopenia	Occasional (5-29%)
HP:0001889	Megaloblastic anemia	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0006515	Interstitial pneumonitis	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0000509	Conjunctivitis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	methotrexate toxicity
Mondo ID	MONDO:0034212
Orphanet	565782
UMLS	C0568062
MedGen	108272
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of primarily extrinsic mechanism › poisoning › chemotherapy-induced toxicity › methotrexate toxicity

Related subtypes (4): 5-fluorouracil poisoning, 5-fluorouracil toxicity, cisplatin toxicity, irinotecan toxicity

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
3520	NM_005957.5(MTHFR):c.665C>T (p.Ala222Val)	MTHFR	drug response	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTHFR	Orphanet:395	Homocystinuria due to methylene tetrahydrofolate reductase deficiency
MTHFR	Orphanet:563609	Isolated anencephaly
MTHFR	Orphanet:563612	Isolated exencephaly

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTHFR	HGNC:7436	ENSG00000177000	P42898	Methylenetetrahydrofolate reductase (NADPH)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTHFR	Methylenetetrahydrofolate reductase (NADPH)	Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTHFR	Enzyme (other)	yes	1.5.1.20	Mehydrof_redctse-like, Fadh2_euk, FAD-linked_oxidoreductase-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
corpus epididymis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTHFR	254	ubiquitous	marker	corpus epididymis, sural nerve, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTHFR	3,492

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTHFR	P42898	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of folate and pterines	1	634.4×	0.006	MTHFR
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.011	MTHFR
Metabolism of vitamins and cofactors	1	116.5×	0.011	MTHFR
Metabolism	1	11.6×	0.086	MTHFR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to vitamin B2	1	8426.0×	0.001	MTHFR
S-adenosylmethionine metabolic process	1	5617.3×	0.001	MTHFR
obsolete methionine biosynthetic process	1	3370.4×	0.001	MTHFR
L-methionine metabolic process	1	2808.7×	0.001	MTHFR
response to folic acid	1	2407.4×	0.001	MTHFR
homocysteine metabolic process	1	1872.4×	0.001	MTHFR
tetrahydrofolate interconversion	1	1685.2×	0.001	MTHFR
heterochromatin organization	1	1296.3×	0.001	MTHFR
response to amino acid	1	991.3×	0.001	MTHFR
response to interleukin-1	1	510.7×	0.003	MTHFR
neural tube closure	1	187.2×	0.006	MTHFR
response to hypoxia	1	95.8×	0.011	MTHFR
response to xenobiotic stimulus	1	69.1×	0.014	MTHFR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTHFR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTHFR	1.5.1.20, 1.5.1.53	methylenetetrahydrofolate reductase [NAD(P)H], methylenetetrahydrofolate reductase (NADPH)

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MTHFR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MTHFR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06123403	Not specified	UNKNOWN	Evaluation of High Dose Methotrexate Toxicity