Autosomal recessive polycystic kidney disease

Summary

Autosomal recessive polycystic kidney disease (MONDO:0009889) is a disease caused by variants in PKD1 and PKHD1, with 8 cohort genes and 6 clinical trials. Top therapeutic interventions include tolvaptan.

At a glance

• Prevalence: 1-9 / 100 000 (Germany) [Orphanet-validated]
• Causal genes: PKD1 (GenCC Definitive), PKHD1 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 5,152
• Phenotypes (HPO): 51
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	5	Germany	Validated

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000105	Enlarged kidney	Very frequent (80-99%)
HP:0000113	Polycystic kidney dysplasia	Very frequent (80-99%)
HP:0000822	Hypertension	Very frequent (80-99%)
HP:0001395	Hepatic fibrosis	Very frequent (80-99%)
HP:0001405	Periportal fibrosis	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0001396	Cholestasis	Frequent (30-79%)
HP:0001409	Portal hypertension	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001562	Oligohydramnios	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001971	Hypersplenism	Frequent (30-79%)
HP:0002040	Esophageal varix	Frequent (30-79%)
HP:0002089	Pulmonary hypoplasia	Frequent (30-79%)
HP:0002612	Congenital hepatic fibrosis	Frequent (30-79%)
HP:0002630	Fat malabsorption	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0002902	Hyponatremia	Frequent (30-79%)
HP:0003774	Stage 5 chronic kidney disease	Frequent (30-79%)
HP:0004905	Low levels of vitamin A	Frequent (30-79%)
HP:0005565	Reduced renal corticomedullary differentiation	Frequent (30-79%)
HP:0006560	Biliary hyperplasia	Frequent (30-79%)
HP:0011040	Abnormality of the intrahepatic bile duct	Frequent (30-79%)
HP:0011892	Low levels of vitamin K	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012202	Increased serum bile acid concentration	Frequent (30-79%)
HP:0030948	Elevated gamma-glutamyltransferase level	Frequent (30-79%)
HP:0100512	Low levels of vitamin D	Frequent (30-79%)
HP:0100513	Low levels of vitamin E	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0001959	Polydipsia	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002243	Protein-losing enteropathy	Occasional (5-29%)
HP:0002791	Hypoventilation	Occasional (5-29%)
HP:0002884	Hepatoblastoma	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0030151	Cholangitis	Occasional (5-29%)
HP:0100520	Oliguria	Occasional (5-29%)
HP:0000347	Micrognathia	Very rare (<1-4%)
HP:0000369	Low-set ears	Very rare (<1-4%)
HP:0000457	Depressed nasal ridge	Very rare (<1-4%)
HP:0001737	Pancreatic cysts	Very rare (<1-4%)
HP:0002108	Spontaneous pneumothorax	Very rare (<1-4%)
HP:0030153	Cholangiocarcinoma	Very rare (<1-4%)
HP:0040064	Abnormality of limbs	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive polycystic kidney disease
Mondo ID	MONDO:0009889
Orphanet	731
DOID	DOID:0110861
ICD-11	1424110943
NCIT	C84579
SNOMED CT	28770003
UMLS	C0085548
MedGen	39076
GARD	0008378
MedDRA	10036047
NORD	831
Is cancer (heuristic)	no

Also known as: AR-PKD · ARPKD · autosomal recessive polycystic kidney · PKHD1 · polycystic kidney and hepatic disease 1 · polycystic kidney disease, autosomal recessive · polycystic kidney disease, infantile type · polycystic kidney disease, infantile, type I

Data availability: 5,152 ClinVar variants · 5 GenCC gene-disease records · 8 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive polycystic kidney disease

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (2): polycystic kidney disease 4, polycystic kidney disease 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

506 likely benign, 32 uncertain significance, 21 pathogenic, 14 likely pathogenic, 14 pathogenic/likely pathogenic, 12 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070083	NM_138694.4(PKHD1):c.4836del (p.Cys1613fs)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066339	NM_138694.4(PKHD1):c.977-1G>A	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066549	NM_138694.4(PKHD1):c.2T>C (p.Met1Thr)	PKHD1	Pathogenic	criteria provided, single submitter
1068071	NM_138694.4(PKHD1):c.9830-2A>G	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069080	NM_138694.4(PKHD1):c.6008del (p.Lys2003fs)	PKHD1	Pathogenic	criteria provided, single submitter
1069641	NM_138694.4(PKHD1):c.8195C>G (p.Ser2732Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070163	NM_138694.4(PKHD1):c.8980C>T (p.Gln2994Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070196	NM_138694.4(PKHD1):c.547C>T (p.Gln183Ter)	PKHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070528	NM_138694.4(PKHD1):c.7529_7530del (p.Ser2510fs)	PKHD1	Pathogenic	criteria provided, single submitter
1070806	NM_138694.4(PKHD1):c.5374del (p.Leu1792fs)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071002	NM_138694.4(PKHD1):c.5695C>T (p.Gln1899Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071279	NC_000006.11:g.(?51612575)(51618161_?)del	PKHD1	Pathogenic	criteria provided, single submitter
1071341	NM_138694.4(PKHD1):c.2664_2665insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGTTGCAGTGAGCCGAGATGGCAGCAGTACAGTCCAGCTTCGGCTCCGCATGAGAGGGAGACCGTGGGGAGAGGGAGACAGAGGGAGAGGGAGAGGGAGCATGATGGTGGAGTTTTT (p.Leu889fs)	PKHD1	Pathogenic	criteria provided, single submitter
1071441	NM_138694.4(PKHD1):c.9210_9223del (p.Gln3070fs)	PKHD1	Pathogenic	criteria provided, single submitter
1071908	NM_138694.4(PKHD1):c.8151del (p.Gly2718fs)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072350	NM_138694.4(PKHD1):c.11403C>A (p.Cys3801Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072516	NM_138694.4(PKHD1):c.2932del (p.Gln978fs)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072788	NM_138694.4(PKHD1):c.8128C>T (p.Gln2710Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073091	NC_000006.11:g.(?51701192)(51701277_?)del	PKHD1	Pathogenic	criteria provided, single submitter
1073092	NC_000006.11:g.(?51637490)(51637597_?)del	PKHD1	Pathogenic	criteria provided, single submitter
1073631	NM_138694.4(PKHD1):c.11408dup (p.Ala3804fs)	PKHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073734	NM_138694.4(PKHD1):c.8863C>T (p.Arg2955Ter)	PKHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073873	NM_138694.4(PKHD1):c.1626_1629del (p.Leu543fs)	PKHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073874	NM_138694.4(PKHD1):c.1197del (p.Leu400fs)	PKHD1	Pathogenic	criteria provided, single submitter
1074162	NM_138694.4(PKHD1):c.10561C>T (p.Gln3521Ter)	PKHD1	Pathogenic	criteria provided, single submitter
1074409	NM_138694.4(PKHD1):c.424del (p.Val142fs)	PKHD1	Pathogenic	criteria provided, single submitter
1074792	NM_138694.4(PKHD1):c.9149del (p.Gly3050fs)	PKHD1	Pathogenic	criteria provided, single submitter
1075305	NM_138694.4(PKHD1):c.1856del (p.Gly619fs)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075810	NM_138694.4(PKHD1):c.3589dup (p.Glu1197fs)	PKHD1	Pathogenic	criteria provided, single submitter
1075837	NM_138694.4(PKHD1):c.484G>T (p.Gly162Ter)	PKHD1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PKD1	Definitive	Autosomal recessive	autosomal recessive polycystic kidney disease	7
PKHD1	Definitive	Autosomal recessive	autosomal recessive polycystic kidney disease	10
PRKD1	Definitive	Autosomal recessive	autosomal recessive polycystic kidney disease	14
DZIP1L	Strong	Autosomal recessive	polycystic kidney disease 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PKHD1	Orphanet:53035	Caroli disease
PKHD1	Orphanet:731	Autosomal recessive polycystic kidney disease
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome
DZIP1L	Orphanet:731	Autosomal recessive polycystic kidney disease
DYNC2H1	Orphanet:474	Jeune syndrome
DYNC2H1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
DYNC2H1	Orphanet:93270	Short rib-polydactyly syndrome, Saldino-Noonan type
DYNC2H1	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
PKD2	Orphanet:730	Autosomal dominant polycystic kidney disease

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	gencc,clinvar
PKHD1	HGNC:9016	ENSG00000170927	P08F94	Fibrocystin	gencc,clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	gencc,clinvar
DZIP1L	HGNC:26551	ENSG00000158163	Q8IYY4	Cilium assembly protein DZIP1L	gencc
CYS1	HGNC:18525	ENSG00000205795	Q717R9	Cystin-1	clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	clinvar
MCM3	HGNC:6945	ENSG00000112118	P25205	DNA replication licensing factor MCM3	clinvar
PKD2	HGNC:9009	ENSG00000118762	Q13563	Polycystin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PKHD1	Fibrocystin	Promotes ciliogenesis in renal epithelial cells and therefore participates in the tubules formation and/ or ensures the maintenance of the architecture of the lumen of the kidney.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…
DZIP1L	Cilium assembly protein DZIP1L	Involved in primary cilium formation.
DYNC2H1	Cytoplasmic dynein 2 heavy chain 1	May function as a motor for intraflagellar retrograde transport.
MCM3	DNA replication licensing factor MCM3	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.
PKD2	Polycystin-2	Forms a nonselective cation channel.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.38

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	2	7.3×	0.114
Kinase	1	3.5×	0.509
Transcription factor	1	1.0×	0.755
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PKHD1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Pectin_lyase_fold/virulence
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE
DZIP1L	Transcription factor	no		Znf_C2H2_type, DZIP1_N, DZIP_RILPL
CYS1	Other/Unknown	no		Cys1
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
MCM3	Other/Unknown	no		MCM_dom, AAA+_ATPase, Mcm3
PKD2	Other/Unknown	no		EF_hand_dom, PKD_2, EF-hand-dom_pair

Expression context

Cohort genes with no expression data: 0.

8 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
kidney epithelium	2
renal medulla	2
ventricular zone	2
bronchial epithelial cell	2
right uterine tube	2
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
metanephros cortex	1
seminal vesicle	1
thoracic aorta	1
sural nerve	1
adult mammalian kidney	1
secondary oocyte	1
embryo	1
ganglionic eminence	1
blood vessel layer	1
calcaneal tendon	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PKHD1	51	tissue_specific	marker	kidney epithelium, renal medulla, metanephros cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta
DZIP1L	215	ubiquitous	marker	right uterine tube, sural nerve, bronchial epithelial cell
CYS1	186	broad	marker	kidney epithelium, renal medulla, adult mammalian kidney
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
MCM3	283	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
PKD2	288	ubiquitous	marker	blood vessel layer, calcaneal tendon, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM3	3,953
PRKD1	2,131
DYNC2H1	1,885
PKD2	1,644
PKD1	1,370
PKHD1	1,211
DZIP1L	914
CYS1	524

Intra-cohort edges

A	B	Sources
CYS1	PKD1	string_interaction
CYS1	PKD2	string_interaction
CYS1	PKHD1	string_interaction
DZIP1L	PKHD1	string_interaction
PKD1	PKD2	biogrid_interaction, intact, string_interaction
PKD1	PKHD1	string_interaction
PKD1	PRKD1	string_interaction
PKD2	PKHD1	string_interaction
PKD2	PRKD1	string_interaction
PKHD1	PRKD1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PKD2	Q13563	31
MCM3	P25205	28
PKD1	P98161	13
DYNC2H1	Q8NCM8	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DZIP1L	Q8IYY4	70.03
PRKD1	Q15139	68.99
CYS1	Q717R9	66.42
PKHD1	P08F94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 8 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
VxPx cargo-targeting to cilium	2	173.0×	0.001	PKD1, PKD2
Trafficking of myristoylated proteins to the cilium	1	380.7×	0.033	CYS1
DNA strand elongation	1	190.3×	0.043	MCM3
Unwinding of DNA	1	146.4×	0.043	MCM3
Activation of the pre-replicative complex	1	54.4×	0.049	MCM3
DNA Replication Pre-Initiation	1	52.9×	0.049	MCM3
Activation of ATR in response to replication stress	1	50.1×	0.049	MCM3
Switching of origins to a post-replicative state	1	50.1×	0.049	MCM3
Synthesis of DNA	1	50.1×	0.049	MCM3
Sphingolipid de novo biosynthesis	1	47.6×	0.049	PRKD1
DNA Replication	1	39.6×	0.049	MCM3
G1/S Transition	1	38.8×	0.049	MCM3
Intraflagellar transport	1	33.4×	0.049	DYNC2H1
Mitotic G1 phase and G1/S transition	1	30.7×	0.049	MCM3
S Phase	1	30.2×	0.049	MCM3
Hedgehog ‘off’ state	1	29.7×	0.049	DYNC2H1
Orc1 removal from chromatin	1	29.7×	0.049	MCM3
Sphingolipid metabolism	1	28.0×	0.049	PRKD1
Assembly of the pre-replicative complex	1	23.2×	0.055	MCM3
G2/M Checkpoints	1	22.4×	0.055	MCM3
Cell Cycle Checkpoints	1	14.8×	0.078	MCM3
Cell Cycle, Mitotic	1	8.0×	0.134	MCM3
Cell Cycle	1	6.0×	0.169	MCM3
Metabolism of lipids	1	5.3×	0.183	PRKD1
Metabolism	1	1.9×	0.417	PRKD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mesonephric tubule development	2	2407.4×	3e-05	PKD1, PKD2
metanephric ascending thin limb development	2	1203.7×	8e-05	PKD1, PKD2
mesonephric duct development	2	963.0×	8e-05	PKD1, PKD2
placenta blood vessel development	2	401.2×	4e-04	PKD1, PKD2
detection of mechanical stimulus	2	343.9×	4e-04	PKD1, PKD2
kidney development	3	60.2×	4e-04	PKD1, PKHD1, DYNC2H1
protein heterotetramerization	2	300.9×	4e-04	PKD1, PKD2
embryonic placenta development	2	218.9×	7e-04	PKD1, PKD2
branching morphogenesis of an epithelial tube	2	209.3×	7e-04	PKD1, PKHD1
neural tube development	2	150.5×	0.001	PKD1, PKD2
spinal cord development	2	145.9×	0.001	PKD1, PKD2
cilium assembly	3	31.5×	0.001	PKHD1, DZIP1L, DYNC2H1
protein localization to cilium	2	114.6×	0.002	DZIP1L, DYNC2H1
regulation of cell adhesion	2	87.5×	0.003	PKD1, PKHD1
cell surface receptor signaling pathway via JAK-STAT	2	83.0×	0.003	PKD1, PKD2
metanephric cortex development	1	2407.4×	0.003	PKD2
metanephric cortical collecting duct development	1	2407.4×	0.003	PKD2
metanephric distal tubule development	1	2407.4×	0.003	PKD2
metanephric distal tubule morphogenesis	1	2407.4×	0.003	PKD1
regulation of cholangiocyte proliferation	1	2407.4×	0.003	PKHD1
determination of left/right symmetry	2	73.0×	0.003	DYNC2H1, PKD2
liver development	2	63.4×	0.003	PKD1, PKD2
calcium ion transmembrane transport	2	60.2×	0.003	PKD1, PKD2
calcium ion transport	2	51.8×	0.004	PKD1, PKD2
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	1203.7×	0.005	PRKD1
renal artery morphogenesis	1	1203.7×	0.005	PKD2
nitrogen cycle metabolic process	1	1203.7×	0.005	PKD1
metanephric smooth muscle tissue development	1	1203.7×	0.005	PKD2
intracellular calcium ion homeostasis	2	41.5×	0.006	PKHD1, PKD2
detection of nodal flow	1	802.5×	0.006	PKD2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 4 of 8 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
PKD1	0	0
PKHD1	0	0
DZIP1L	0	0
CYS1	0	0
DYNC2H1	0	0
MCM3	0	0
PKD2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27
PKD2	12	Binding:12
MCM3	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

26 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PKD1
D	Druggable family + AlphaFold only, no drug	1	PKHD1
E	Difficult family or no structure, no drug	5	DZIP1L, CYS1, DYNC2H1, MCM3, PKD2

Undrugged target profiles

7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
PKHD1	0	—
DZIP1L	0	—
CYS1	0	—
DYNC2H1	0	—
MCM3	10	—
PKD2	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04782258	PHASE3	RECRUITING	A Study to See Iftolvaptan is Safe in Infants and Children Who at Enrollment Are 28 Days to Less Than 18 Years Old withAutosomal Recessive Polycystic Kidney Disease (ARPKD)
NCT04786574	PHASE3	WITHDRAWN	A Study to See if Tolvaptan Can Delay Dialysis in Infants and Children Who at Enrollment Are 28 Days to Less Than 12 Weeks Old With Autosomal Recessive Polycystic Kidney Disease (ARPKD)
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06147414	Not specified	RECRUITING	Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders
NCT07201025	Not specified	RECRUITING	Imaging Assessments of ARPKD Kidney Disease Progression

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TOLVAPTAN	4	2
CHEMBL4303142	0	1