PRKD1

Chr 14AD

protein kinase D1

Also known as: CHDED, PKC-MU, PKCM, PKD, PKD1, PRKCM

NCBI Gene: 5587 ENSG00000184304 UniProt: Q15139 OMIM: 605435

The protein is a serine/threonine kinase that regulates Golgi membrane integrity and protein transport, cell signaling pathways including MAPK and NF-kappa-B, and cardiac function. Mutations cause congenital heart defects and ectodermal dysplasia with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a serine/threonine protein kinase involved in many cellular processes, including Golgi body membrane integrity and transport, cell migration and differentiation, MAPK8/JNK1 and Ras pathway signaling, MAPK1/3 (ERK1/2) pathway signaling, cell survival, and regulation of cell shape and adhesion. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.621 OMIM phenotype

Clinical Summary— PRKD1

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Gene-Disease Validity (ClinGen)

congenital heart disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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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

10 unique Pathogenic / Likely Pathogenic· 190 VUS of 266 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.000

Z-score 3.52

OE 0.42 (0.29–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.43Z-score

OE missense 0.82 (0.76–0.89)

411 obs / 501.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.29–0.62)

0≤0.351.4

Missense OE?0.82 (0.76–0.89)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 18 / 42.9Missense obs/exp: 411 / 501.2Syn Z: -0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePRKD1-related syndromic congenital heart defectsOTHERAD

This gene — mechanism propensity

0.5477th %ile

GOF

0.6346th %ile

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOF1 literature citation

LOF40% of P/LP variants are LoF

Literature Evidence

GOFFunctional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity.1

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

References

1.PMID 32817298 ↗

ClinVar Variant Classifications

266 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic8

VUS190

Likely Benign43

Benign16

Conflicting7

Pathogenic

Likely Pathogenic

190

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	4	4	0	0	8
VUS	11	177	1	1	190
Likely Benign	1	13	5	24	43
Benign	0	5	7	4	16
Conflicting	—				7
Total	16	201	13	29	266

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap PRKD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →