PKN1

Chr 19

protein kinase N1

Also known as: DBK, PAK-1, PAK1, PKN, PKN-ALPHA, PRK1, PRKCL1

NCBI Gene: 5585 ENSG00000123143 UniProt: Q16512 OMIM: 601032

PKN1 encodes a serine/threonine protein kinase that regulates the actin cytoskeleton and intermediate filaments by phosphorylating proteins including vimentin, neurofilament proteins, and tau, and also functions in transcriptional regulation. Mutations cause autosomal dominant intellectual disability with microcephaly and seizures, typically presenting in early childhood. The gene shows significant constraint against loss-of-function variants (LOEUF = 0.39), consistent with its role in neurodevelopmental disease.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the protein kinase C superfamily. This kinase is activated by Rho family of small G proteins and may mediate the Rho-dependent signaling pathway. This kinase can be activated by phospholipids and by limited proteolysis. The 3-phosphoinositide dependent protein kinase-1 (PDPK1/PDK1) is reported to phosphorylate this kinase, which may mediate insulin signals to the actin cytoskeleton. The proteolytic activation of this kinase by caspase-3 or related proteases during apoptosis suggests its role in signal transduction related to apoptosis. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — PKN1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.204

Z-score 4.82

OE 0.24 (0.15–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.34Z-score

OE missense 0.84 (0.78–0.91)

496 obs / 587.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.15–0.39)

0≤0.351.4

Missense OE?0.84 (0.78–0.91)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 11 / 46.4Missense obs/exp: 496 / 587.7Syn Z: 0.11

Background carrier burden — how many people carry a rare variant somewhere in PKN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 34

1,552 rare PASS variants

Rare truncating (LoF)

1 in 600

191 rare PASS variants

Rare synonymous (reference)

1 in 49

672 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PKN1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 41	1 in 800
South Asian	~43k	1 in 27	1 in 420
Remaining (unassigned)	~30k	1 in 27	1 in 380
European (Finnish)	~27k	1 in 89	1 in 1,600
Admixed American	~22k	1 in 32	1 in 870
African / African American	~21k	1 in 30	1 in 500
East Asian	~20k	1 in 34	1 in 460
Ashkenazi Jewish	~13k	1 in 88	1 in 530
Middle Eastern	~2,884	1 in 25	1 in 450

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 21 of 22 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 22.? see exons ↓