PDK1

Chr 2

pyruvate dehydrogenase kinase 1

NCBI Gene: 5163 ENSG00000152256 UniProt: Q15118 OMIM: 602524

Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2013]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.81

Clinical Summary— PDK1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 53 VUS of 76 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PDK1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.26

OE 0.50 (0.32–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.15Z-score

OE missense 0.79 (0.70–0.89)

185 obs / 234.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.32–0.81)

0≤0.351.4

Missense OE?0.79 (0.70–0.89)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 12 / 24.0Missense obs/exp: 185 / 234.4Syn Z: 0.47

This gene — mechanism propensity

0.7325th %ile

GOF

0.6249th %ile

LOF

0.3161th %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

76 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS53

Likely Benign1

Conflicting1

Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	0	53	0	0	53
Likely Benign	0	0	0	1	1
Benign	0	0	0	0	0
Conflicting	—				1
Total	0	53	1	1	56

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap PDK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →