PKHD1

Chr 6AR

PKHD1 ciliary IPT domain containing fibrocystin/polyductin

Also known as: ARPKD, FCYT, FPC, PCYT, PKD4, TIGM1

NCBI Gene: 5314ENSG00000170927UniProt: P08F94

The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Polycystic kidney disease 4, with or without hepatic diseaseMIM #263200
AR
6640
ClinVar variants
70
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— PKHD1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
70 Pathogenic / Likely Pathogenic· 323 VUS of 6640 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.68LOEUF
pLI 0.000
Z-score 5.28
OE 0.58 (0.49–0.68)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.98Z-score
OE missense 1.06 (1.02–1.10)
2245 obs / 2117.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.58 (0.49–0.68)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.06 (1.02–1.10)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 107 / 184.4Missense obs/exp: 2245 / 2117.9Syn Z: -0.56

ClinVar Variant Classifications

6640 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic49
VUS323
Likely Benign86
Benign1
Conflicting2
21
Pathogenic
49
Likely Pathogenic
323
VUS
86
Likely Benign
1
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
0
10
0
21
Likely Pathogenic
26
5
18
0
49
VUS
2
254
40
27
323
Likely Benign
0
6
33
47
86
Benign
0
0
1
0
1
Conflicting
—2
Total3926510274482

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

View in ClinVar →

Protein Context — Lollipop Plot

PKHD1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PKHD1-related polycystic kidney disease

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Polycystic kidney disease 4, with or without hepatic disease

MIM #263200

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Polycystic kidney disease.
Harris PC et al.·Annu Rev Med
2009Review
Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.
Domingo-Gallego A et al.·Nephrol Dial Transplant
2022
Autosomal Recessive Polycystic Kidney Disease: Diagnosis, Prognosis, and Management.
Burgmaier K et al.·Adv Kidney Dis Health
2023Review
Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.
Yang H et al.·Adv Kidney Dis Health
2023Review
PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis.
Gunay-Aygun M et al.·Mol Genet Metab
2010
Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD).
Bergmann C et al.·Kidney Int
2005Cohort
Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants.
Burgmaier K et al.·Kidney Int
2021Cohort
Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease.
Chang AR et al.·JAMA
2022
Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing.
Mallawaarachchi AC et al.·Eur J Hum Genet
2021
Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.
Durkie M et al.·Genet Med
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Clinical characteristics and genotype-phenotype correlation for patients with autosomal recessive polycystic kidney disease and PKHD1 mutations.
Wang Q et al.·Clin Nephrol
2026Cohort
Delineating the Genetic Basis of RNF213-related vasculopathies: The association of PKHD1 variants with bilateral cerebral vasculopathy.
Ishigami D et al.·Eur J Hum Genet
2026
Next-Generation Sequencing Defines a Molecularly Confirmed ARPKD Core Within the Broader PKHD1-Associated Disease Spectrum.
Lapunzina-Soler P et al.·Genes (Basel)
2026
Novel compound heterozygous PKHD1 mutations in a Chinese ARPKD pedigree and analysis of genotype-phenotype correlations.
Zhao J et al.·Front Med (Lausanne)
2026🔓 Open Access
Identification of Pathogenic PKHD1 Variants in Infants with Autosomal Recessive Polycystic Kidney Disease from the Dhofar Region, Oman.
Al Alawi I et al.·F1000Res
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Invasive PreNatal Diagnosis in a Context of Family History of Single-gene Disorders, IncludingSickle Cell DiseaseCystic Fibrosis

Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders

RECRUITING
NCT06147414Assistance Publique - Hôpitaux de ParisStarted 2024-10-23
Blood sample
Adenine Phosphoribosyltransferase DeficiencyAH AmyloidosisAHL Amyloidosis

National Registry of Rare Kidney Diseases

RECRUITING
NCT06065852UK Kidney AssociationStarted 2009-11-06
Hepato/Renal Fibrocystic DiseaseAutosomal Recessive Polycystic Kidney DiseaseJoubert Syndrome

ARPKD Database Study

RECRUITING
NCT01401998Children's Hospital of PhiladelphiaStarted 2011-06

External Resources

Links to major genomics databases and tools