thiopurine S-methyltransferase deficiency

Summary

thiopurine S-methyltransferase deficiency (MONDO:0012503) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thiopurine S-methyltransferase deficiency
Mondo ID	MONDO:0012503
MeSH	C536512
OMIM	610460
Orphanet	3315
DOID	DOID:0061004, DOID:0080172
ICD-11	1916778396
NCIT	C4389
SNOMED CT	238012003
UMLS	C0342801
MedGen	83352
GARD	0005173
Is cancer (heuristic)	no

Also known as: 6-mercaptopurine sensitivity · inborn error of thiopurine S-methyltransferase activity · inborn thiopurine S-methyltransferase activity disorder · poor metabolism of thiopurines-1 · rare inborn error of thiopurine S-methyltransferase activity · thiopurine methyltransferase deficiency · thiopurine S methyltranferase deficiency · thiopurine S-methyltransferase deficiency · THPM1 · TPMT deficiency

Data availability: 7 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › thiopurine metabolic disease › thiopurine S-methyltransferase deficiency

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

7 retrieved; paginated sample, class counts are floors:

5 drug response, 1 likely benign; other, 1 benign/likely benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
12722	TPMT*3A		drug response	no assertion criteria provided
12721	NM_000367.2(TPMT):c.238G>C (p.Ala80Pro)	TPMT	drug response	no assertion criteria provided
12723	NM_000367.5(TPMT):c.626-1G>A	TPMT	drug response	no assertion criteria provided
12726	NM_000367.5(TPMT):c.644G>A (p.Arg215His)	TPMT	drug response	no assertion criteria provided
12727	NM_000367.5(TPMT):c.500C>G (p.Ala167Gly)	TPMT	drug response	no assertion criteria provided
12725	NM_000367.5(TPMT):c.719A>G (p.Tyr240Cys)	TPMT	Likely benign; other	criteria provided, multiple submitters, no conflicts
37126	NM_000367.5(TPMT):c.460G>A (p.Ala154Thr)	TPMT	Benign/Likely benign; other	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

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
TPMT	HGNC:12014	ENSG00000137364	P51580	Thiopurine S-methyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPMT	Thiopurine S-methyltransferase	Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S-adenosyl-L-methionine as the methyl donor.

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)
TPMT	Enzyme (other)	yes	2.1.1.67	TPMT, Thiopurine_S-MeTrfase, SAM-dependent_MTases_sf

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
buccal mucosa cell	1
tendon of biceps brachii	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPMT	270	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPMT	3,372

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TPMT	P51580	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Defective TPMT causes TPMT deficiency	1	11420.0×	3e-04	TPMT
Methylation	1	815.7×	0.002	TPMT
Azathioprine ADME	1	496.5×	0.002	TPMT

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
xenobiotic catabolic process	1	561.7×	0.004	TPMT
nucleobase-containing compound metabolic process	1	526.6×	0.004	TPMT
methylation	1	170.2×	0.007	TPMT
xenobiotic metabolic process	1	149.1×	0.007	TPMT

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPMT	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SINEFUNGIN	2	TPMT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TPMT	6	Binding:3, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPMT	2.1.1.67	thiopurine S-methyltransferase

Pharmacogenomics

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

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
TPMT	1

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
SINEFUNGIN	2	TPMT

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	1	TPMT
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.