PKD2

Chr 4AD

polycystin 2, transient receptor potential cation channel

Also known as: APKD2, PC2, PKD4, Pc-2, TRPP2

NCBI Gene: 5311 ENSG00000118762 UniProt: Q13563

The protein encoded by this gene functions as a calcium-permeable cation channel in renal epithelial cells and primary cilia, where it is involved in fluid-flow mechanosensation and calcium signaling. Mutations cause autosomal dominant polycystic kidney disease type 2, which primarily affects the kidneys through progressive cyst formation. This gene is highly constrained against loss-of-function variants (LOEUF 0.497), indicating that complete loss of protein function is likely incompatible with normal development.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

Polycystic kidney disease 2MIM #613095

Active trials

Pubs (1 yr)

P/LP submissions

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P/LP missense

0.50

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— PKD2

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Gene-Disease Validity (ClinGen)

autosomal dominant polycystic kidney disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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Clinical Trials

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

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GeneReview available — PKD2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.50LOEUF

pLI 0.000

Z-score 4.36

OE 0.33 (0.22–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

0.27Z-score

OE missense 0.96 (0.89–1.04)

449 obs / 465.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.33 (0.22–0.50)

0≤0.351.4

Missense OE0.96 (0.89–1.04)

0≤0.61.4

Synonymous OE1.18

0≤1.21.6

LoF obs/exp: 16 / 48.9Missense obs/exp: 449 / 465.5Syn Z: -1.91

0.76top 25%

GOF

0.84top 5%

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative 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.

GOFprediction above median · 1 literature citation

DNprediction above median

LOF1 literature citation · LOEUF 0.50

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.

Literature Evidence

GOFAutosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 gene, encoding the polycystic kidney disease protein polycystin-1 and the transient receptor potential channel polycystin-2 (also known as TRPP2), respectively.PMID:31441214

LOFA loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2.PMID:10417277

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