PDPK1

Chr 16

3-phosphoinositide dependent protein kinase 1

Also known as: PDK1, PRO0461

NCBI Gene: 5170 ENSG00000140992 OMIM: 605213

The protein encoded by this gene is a master serine/threonine kinase that phosphorylates and activates multiple AGC family kinases including AKT, playing a central role in insulin signaling and controlling cell proliferation, survival, glucose uptake, and cardiac homeostasis. Mutations cause a neurodevelopmental disorder with early infantile epileptic encephalopathy and focal cortical dysplasia, inherited in an autosomal recessive pattern. This gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.29), indicating intolerance to haploinsufficiency in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Enables 3-phosphoinositide-dependent protein kinase activity; phospholipase activator activity; and phospholipase binding activity. Involved in several processes, including cell surface receptor signaling pathway; intracellular signaling cassette; and regulation of signal transduction. Acts upstream of or within intracellular signal transduction. Located in cell projection; cytosol; and plasma membrane. Implicated in prostate cancer. Biomarker of lung non-small cell carcinoma. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.29

Clinical Summary— PDPK1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.980

Z-score 3.52

OE 0.06 (0.02–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.01Z-score

OE missense 0.56 (0.48–0.67)

95 obs / 168.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.29)

0≤0.351.4

Missense OE?0.56 (0.48–0.67)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 1 / 16.4Missense obs/exp: 95 / 168.4Syn Z: -0.30

This gene — mechanism propensity

0.3693th %ile

GOF

0.4974th %ile

LOF

0.68top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.29

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.