TPK1

Chr 7AR

thiamin pyrophosphokinase 1

Also known as: HTPK1, PP20, THMD5

NCBI Gene: 27010 ENSG00000196511 UniProt: Q9H3S4 OMIM: 606370

The protein catalyzes the phosphorylation of thiamine to thiamine pyrophosphate (TPP), a critical cofactor for mitochondrial pyruvate dehydrogenase and enzymes involved in glycolysis and energy production. Mutations cause thiamine metabolism dysfunction syndrome 5, characterized by episodic encephalopathy, and follow autosomal recessive inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.7), reflecting its essential role in cellular energy metabolism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.701 OMIM phenotype

Clinical Summary— TPK1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

44 unique Pathogenic / Likely Pathogenic· 129 VUS of 335 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TPK1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.091

Z-score 2.33

OE 0.31 (0.15–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.34Z-score

OE missense 0.92 (0.79–1.07)

121 obs / 132.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.15–0.70)

0≤0.351.4

Missense OE?0.92 (0.79–1.07)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 4 / 13.1Missense obs/exp: 121 / 132.1Syn Z: 0.34

This gene — mechanism propensity

0.6746th %ile

GOF

0.4677th %ile

LOF

0.2287th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

335 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28

Likely Pathogenic16

VUS129

Likely Benign120

Benign29

Conflicting6

Pathogenic

Likely Pathogenic

129

VUS

120

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	4	14	0	28
Likely Pathogenic	8	5	3	0	16
VUS	0	106	23	0	129
Likely Benign	0	6	60	54	120
Benign	0	1	28	0	29
Conflicting	—				6
Total	18	122	128	54	328

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

View in ClinVar →

54 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap TPK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →