TPK1

Chr 7AR

thiamin pyrophosphokinase 1

Also known as: HTPK1, PP20, THMD5

NCBI Gene: 27010ENSG00000196511UniProt: Q9H3S4

The protein encoded by this gene functions as a homodimer and catalyzes the conversion of thiamine to thiamine pyrophosphate, a cofactor for some enzymes of the glycolytic and energy production pathways. Defects in this gene are a cause of thiamine metabolism dysfunction syndrome-5. [provided by RefSeq, Apr 2017]

Primary Disease Associations & Inheritance

Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)MIM #614458
AR
392
ClinVar variants
97
Pathogenic / LP
0.09
pLI score
0
Active trials
Clinical Summary— TPK1
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 140 VUS of 392 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.70LOEUF
pLI 0.091
Z-score 2.33
OE 0.31 (0.15–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.34Z-score
OE missense 0.92 (0.79–1.07)
121 obs / 132.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.31 (0.15–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.79–1.07)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 4 / 13.1Missense obs/exp: 121 / 132.1Syn Z: 0.34

ClinVar Variant Classifications

392 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic79
Likely Pathogenic18
VUS140
Likely Benign120
Benign29
Conflicting6
79
Pathogenic
18
Likely Pathogenic
140
VUS
120
Likely Benign
29
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
4
67
0
79
Likely Pathogenic
7
5
6
0
18
VUS
0
104
36
0
140
Likely Benign
0
6
60
54
120
Benign
0
1
28
0
29
Conflicting
—6
Total1512019754392

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TPK1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)

MIM #614458

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TPK1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Multiomics-based molecular subtyping based on the commensal microbiome predicts molecular characteristics and the therapeutic response in breast cancer.
Qin W et al.·Mol Cancer
2024
Treatment of genetic defects of thiamine transport and metabolism.
Ortigoza-Escobar JD et al.·Expert Rev Neurother
2016Review
Plasma proteomic profiling reveals Parkinson's disease-associated proteins: A UK Biobank study.
Jiao X et al.·Parkinsonism Relat Disord
2025
Novel Synonymous and Deep Intronic Variants Causing Primary and Secondary Pyruvate Dehydrogenase Complex Deficiency.
Bruhn H et al.·Hum Mutat
2024Case report
Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations.
Banka S et al.·Mol Genet Metab
2014Case report
Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies.
Marcé-Grau A et al.·J Inherit Metab Dis
2019Review
Thiamine metabolism dysfunction syndrome 5 (THMD5) mimicking acute disseminated encephalomyelitis.
Thompson ZE et al.·Am J Med Genet A
2023Case report
A framework for exhaustively mapping functional missense variants.
Weile J et al.·Mol Syst Biol
2017Functional
Thiamine phosphokinase deficiency and mutation in TPK1 presenting as biotin responsive basal ganglia disease.
Nyhan WL et al.·Clin Chim Acta
2019Case report
Clinical and molecular characterization of pediatric mitochondrial disorders in south of China.
Hu C et al.·Eur J Med Genet
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools