PKD1

Chr 16AD

polycystin 1, transient receptor potential channel interacting

Also known as: PBP, PC1, Pc-1, TRPP1, eliosin

NCBI Gene: 5310 ENSG00000008710 UniProt: P98161 OMIM: 601313

The encoded protein forms a heteromeric calcium-permeable ion channel with PKD2 that regulates intracellular calcium homeostasis, controls cilium length in renal epithelium, and is involved in fluid-flow mechanosensation and renal tubulogenesis. Mutations cause autosomal dominant polycystic kidney disease type 1, characterized by progressive growth of fluid-filled cysts that replace normal renal tissue and lead to end-stage renal failure. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.179), indicating high biological constraint.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.182 OMIM phenotypes

Clinical Summary— PKD1

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Gene-Disease Validity (ClinGen)

autosomal recessive polycystic kidney disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 9.96

OE 0.12 (0.08–0.18)

Highly constrained

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

Missense Constraint?

-4.32Z-score

OE missense 1.23 (1.20–1.27)

3329 obs / 2697.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.12 (0.08–0.18)

0≤0.351.4

Missense OE?1.23 (1.20–1.27)

0≤0.61.4

Synonymous OE?1.63

0≤1.21.6

LoF obs/exp: 18 / 149.4Missense obs/exp: 3329 / 2697.2Syn Z: -17.86

This gene — mechanism propensity

0.4190th %ile

GOF

0.6052th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.18 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNIn the present study, we report the generation of transgenic mice with inducible conditional expression of a dominant-negative PKD1kd (kinase-dead PKD1) protein in skeletal muscle to assess the role of PKD in muscle function.1

GOFThis study not only produced an invaluable and first PKD model to evaluate molecular pathogenesis and therapies but also provides evidence that gain of function could be a pathogenetic mechanism in ADPKD.2

LOFAn Mekk1-p53 interaction at the PKD1 promoter suggests a new mechanism by which abnormally elevated stress-pathway stimuli might directly down-regulate the PKD1 gene, possibly causing haploinsufficiency and cyst formation.3

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

References

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PKD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

RADIOLOGICAL AND CLINICAL EVALUATION OF RENAL EMBOLIZATION USING EVOH IN DIALYSIS PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: A PROSPECTIVE LONGITUDINAL OBSERVATIONAL STUDY

RECRUITING

NCT07535385Fondazione IRCCS Policlinico San Matteo di PaviaStarted 2020-08-17

Kidney Diseases

Safety of RotigotiNe in Patients With Autosomal Dominant Polycystic Kidney Disease

RECRUITING

NCT06291116Phase PHASE2University Hospital, RouenStarted 2026-05-12

standard care + rotigotine at 4 mg/24h for 24 months.standard care for 24 months.

Variant Nucleotide

Solving Challenging Diagnoses Through Ultra-long Read Sequencing

ACTIVE NOT RECRUITING

NCT06775613Phase NAIRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2023-03-10

Long-read sequencing