Polycystic kidney disease 4

Summary

Polycystic kidney disease 4 (MONDO:0033004) is a disease caused by PKHD1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: PKHD1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,861

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polycystic kidney disease 4
Mondo ID	MONDO:0033004
OMIM	263200
DOID	DOID:0080212
UMLS	C4540575
MedGen	1621793
GARD	0006168
Is cancer (heuristic)	no

Also known as: PKD3 · PKD4 · polycystic kidney disease 4, with or without hepatic disease

Data availability: 1,861 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 › polycystic kidney disease 4

Related subtypes (1): 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:

170 likely pathogenic, 136 uncertain significance, 82 pathogenic/likely pathogenic, 75 conflicting classifications of pathogenicity, 60 likely benign, 32 pathogenic, 28 benign, 17 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
1177406	NM_138694.4(PKHD1):c.4644del (p.Tyr1549fs)	LOC126859690	Pathogenic	criteria provided, multiple submitters, no conflicts
1323462	NM_138694.4(PKHD1):c.4993C>T (p.Gln1665Ter)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1369556	NM_138694.4(PKHD1):c.4926_4932del (p.Leu1643fs)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1408016	NM_138694.4(PKHD1):c.4816del (p.Val1606fs)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451341	NM_138694.4(PKHD1):c.4838G>A (p.Cys1613Tyr)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451852	NM_138694.4(PKHD1):c.4660dup (p.Tyr1554fs)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
196807	NM_138694.4(PKHD1):c.5060T>C (p.Ile1687Thr)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444187	NM_138694.4(PKHD1):c.5174G>C (p.Trp1725Ser)	LOC126859690	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064648	NM_138694.3:c.(?5909)(12225_?)del	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
1069641	NM_138694.4(PKHD1):c.8195C>G (p.Ser2732Ter)	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
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
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
1075305	NM_138694.4(PKHD1):c.1856del (p.Gly619fs)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076511	NM_138694.4(PKHD1):c.1992G>A (p.Trp664Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076940	NM_138694.4(PKHD1):c.10134G>A (p.Trp3378Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179144	NM_138694.4(PKHD1):c.1854del (p.Gly619fs)	PKHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1180650	NM_138694.4(PKHD1):c.8642+1G>T	PKHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1210016	NM_138694.4(PKHD1):c.8302+2T>C	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323459	NM_138694.4(PKHD1):c.8208del (p.Trp2736fs)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323460	NM_138694.4(PKHD1):c.470dup (p.Trp158fs)	PKHD1	Pathogenic	criteria provided, single submitter
1323461	NM_138694.4(PKHD1):c.8554+1G>A	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323463	NM_138694.4(PKHD1):c.8069G>A (p.Trp2690Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324919	NM_138694.4(PKHD1):c.2854G>T (p.Gly952Ter)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1347236	NM_138694.4(PKHD1):c.9464A>G (p.Tyr3155Cys)	PKHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 7 · 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
PKHD1	Definitive	Autosomal recessive	autosomal recessive polycystic kidney disease	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PKHD1	Orphanet:53035	Caroli disease
PKHD1	Orphanet:731	Autosomal recessive polycystic kidney disease
SHOC2	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair
POT1	Orphanet:251627	Oligodendroglioma
POT1	Orphanet:251630	Anaplastic oligodendroglioma
POT1	Orphanet:618	Familial melanoma
POT1	Orphanet:67038	B-cell chronic lymphocytic leukemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PKHD1	HGNC:9016	ENSG00000170927	P08F94	Fibrocystin	gencc,clinvar
SHOC2	HGNC:15454	ENSG00000108061	Q9UQ13	Leucine-rich repeat protein SHOC-2	clinvar
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SHOC2	Leucine-rich repeat protein SHOC-2	Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway.
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PKHD1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Pectin_lyase_fold/virulence
SHOC2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
kidney epithelium	1
metanephros cortex	1
renal medulla	1
bone marrow	1
sural nerve	1
germinal epithelium of ovary	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PKHD1	51	tissue_specific	marker	kidney epithelium, renal medulla, metanephros cortex
SHOC2	299	ubiquitous	marker	calcaneal tendon, sural nerve, bone marrow
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHOC2	2,149
POT1	1,842
PKHD1	1,211

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POT1	Q9NUX5	14
SHOC2	Q9UQ13	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PKHD1	P08F94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by MRAS-complex mutants	1	1427.5×	0.011	SHOC2
SHOC2 M1731 mutant abolishes MRAS complex function	1	713.8×	0.011	SHOC2
Gain-of-function MRAS complexes activate RAF signaling	1	713.8×	0.011	SHOC2
Telomere C-strand synthesis initiation	1	407.9×	0.011	POT1
Processive synthesis on the C-strand of the telomere	1	380.7×	0.011	POT1
Telomere C-strand (Lagging Strand) Synthesis	1	380.7×	0.011	POT1
Removal of the Flap Intermediate from the C-strand	1	317.2×	0.011	POT1
Telomere Extension By Telomerase	1	228.4×	0.013	POT1
Polymerase switching on the C-strand of the telomere	1	211.5×	0.013	POT1
RAF activation	1	167.9×	0.015	SHOC2
Oncogenic MAPK signaling	1	124.1×	0.017	SHOC2
Packaging Of Telomere Ends	1	109.8×	0.017	POT1
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.017	POT1
Cleavage of the damaged purine	1	102.0×	0.017	POT1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.017	POT1
Cleavage of the damaged pyrimidine	1	92.1×	0.017	POT1
Inhibition of DNA recombination at telomere	1	84.0×	0.017	POT1
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.017	POT1
Meiotic synapsis	1	70.5×	0.019	POT1
MAPK1/MAPK3 signaling	1	65.6×	0.019	SHOC2
MAPK family signaling cascades	1	51.4×	0.023	SHOC2
RAF/MAP kinase cascade	1	30.5×	0.037	SHOC2
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.038	SHOC2
Disease	1	6.5×	0.153	SHOC2
Signal Transduction	1	5.1×	0.187	SHOC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of DNA strand elongation	1	5617.3×	0.002	POT1
cellular response to growth hormone stimulus	1	5617.3×	0.002	SHOC2
regulation of cholangiocyte proliferation	1	5617.3×	0.002	PKHD1
positive regulation of telomeric D-loop disassembly	1	5617.3×	0.002	POT1
telomere assembly	1	1404.3×	0.006	POT1
regulation of double-strand break repair via nonhomologous end joining	1	1123.5×	0.006	POT1
regulation of telomere maintenance via telomerase	1	936.2×	0.006	POT1
regulation of establishment of planar polarity	1	936.2×	0.006	PKHD1
establishment of protein localization to telomere	1	702.2×	0.006	POT1
cyclic-GMP-AMP transmembrane import across plasma membrane	1	702.2×	0.006	SHOC2
telomeric D-loop disassembly	1	624.1×	0.006	POT1
homeostatic process	1	561.7×	0.006	PKHD1
establishment of centrosome localization	1	561.7×	0.006	PKHD1
negative regulation of neural precursor cell proliferation	1	510.7×	0.006	SHOC2
regulation of cell-matrix adhesion	1	432.1×	0.006	PKHD1
telomere capping	1	432.1×	0.006	POT1
nerve growth factor signaling pathway	1	432.1×	0.006	SHOC2
regulation of cell-cell adhesion	1	401.2×	0.006	PKHD1
negative regulation of epithelial cell apoptotic process	1	401.2×	0.006	PKHD1
epithelial cell morphogenesis	1	312.1×	0.007	PKHD1
regulation of TOR signaling	1	312.1×	0.007	PKHD1
positive regulation of Ras protein signal transduction	1	295.6×	0.007	SHOC2
telomere maintenance via telomerase	1	244.2×	0.007	POT1
regulation of centrosome duplication	1	244.2×	0.007	PKHD1
negative regulation of telomere maintenance via telomerase	1	244.2×	0.007	POT1
positive regulation of telomere maintenance via telomerase	1	244.2×	0.007	POT1
branching morphogenesis of an epithelial tube	1	244.2×	0.007	PKHD1
cell-cell junction organization	1	208.1×	0.008	PKHD1
regulation of ERK1 and ERK2 cascade	1	193.7×	0.008	PKHD1
positive regulation of telomere maintenance	1	170.2×	0.009	POT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PKHD1	0	0
SHOC2	0	0
POT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
POT1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PKHD1
E	Difficult family or no structure, no drug	2	SHOC2, POT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKHD1	0	—
SHOC2	0	—
POT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.