Familial cystic renal disease

Summary

Familial cystic renal disease (MONDO:0019741) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial cystic renal disease
Mondo ID	MONDO:0019741
Orphanet	93587
UMLS	C5680285
MedGen	1842297
GARD	0019228
Is cancer (heuristic)	no

Also known as: hereditary cystic kidney disease

Data availability: 16 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › cystic kidney disease › familial cystic renal disease

Related subtypes (3): non-congenital cyst of kidney, medullary sponge kidney, multicystic dysplastic kidney

Subtypes (4): autosomal dominant medullary cystic kidney disease with or without hyperuricemia, autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis, adult familial nephronophthisis-spastic quadriparesia syndrome, polycystic kidney disease

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

16 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 2 uncertain significance, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
280116	NM_024079.5(ALG8):c.1090C>T (p.Arg364Ter)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
492977	NM_024079.5(ALG8):c.535C>T (p.Arg179Ter)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956334	NM_024079.5(ALG8):c.981dup (p.Val328fs)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96090	NM_024079.5(ALG8):c.121C>T (p.Arg41Ter)	ALG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3906840	NM_024740.2(ALG9):c.1695G>A (p.Trp565Ter)	ALG9	Pathogenic	criteria provided, single submitter
3906843	NM_024740.2:c.896_1602del	ALG9	Pathogenic	criteria provided, single submitter
1300719	NM_138694.4(PKHD1):c.8829dup (p.Ile2944fs)	PKHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
3767382	NM_138694.4(PKHD1):c.4_11del (p.Thr2fs)	PKHD1	Pathogenic	criteria provided, single submitter
3767383	NM_138694.4(PKHD1):c.8916del (p.Ser2973fs)	PKHD1	Pathogenic	criteria provided, single submitter
3574039	NM_024079.5(ALG8):c.1114dup (p.Ser372fs)	ALG8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3906841	NM_024079.5(ALG8):c.547-2A>G	ALG8	Likely pathogenic	criteria provided, single submitter
3906842	NM_024079.5(ALG8):c.964C>T (p.Gln322Ter)	ALG8	Likely pathogenic	criteria provided, single submitter
492976	NM_024079.5(ALG8):c.1038+1G>T	ALG8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
593252	NM_178170.3(NEK8):c.133C>T (p.Arg45Trp)	NEK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2443125	NM_024740.2(ALG9):c.334C>T (p.Arg112Cys)	ALG9	Uncertain significance	criteria provided, multiple submitters, no conflicts
971691	NM_178170.3(NEK8):c.1166C>T (p.Ser389Leu)	NEK8	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEK8	Orphanet:294415	Renal-hepatic-pancreatic dysplasia
NEK8	Orphanet:730	Autosomal dominant polycystic kidney disease
NEK8	Orphanet:93591	Infantile nephronophthisis
ALG9	Orphanet:730	Autosomal dominant polycystic kidney disease
ALG9	Orphanet:79328	ALG9-CDG
NEK9	Orphanet:464366	NEK9-related lethal skeletal dysplasia
NEK9	Orphanet:64754	Nevus comedonicus syndrome
ALG8	Orphanet:2924	Isolated polycystic liver disease
ALG8	Orphanet:79325	ALG8-CDG
PKHD1	Orphanet:53035	Caroli disease
PKHD1	Orphanet:731	Autosomal recessive polycystic kidney disease

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NEK8	HGNC:13387	ENSG00000160602	Q86SG6	Serine/threonine-protein kinase Nek8	clinvar
ALG9	HGNC:15672	ENSG00000086848	Q9H6U8	Alpha-1,2-mannosyltransferase ALG9	clinvar
NEK9	HGNC:18591	ENSG00000119638	Q8TD19	Serine/threonine-protein kinase Nek9	clinvar
ALG8	HGNC:23161	ENSG00000159063	Q9BVK2	Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase	clinvar
PKHD1	HGNC:9016	ENSG00000170927	P08F94	Fibrocystin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEK8	Serine/threonine-protein kinase Nek8	Required for renal tubular integrity.
ALG9	Alpha-1,2-mannosyltransferase ALG9	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
NEK9	Serine/threonine-protein kinase Nek9	Pleiotropic regulator of mitotic progression, participating in the control of spindle dynamics and chromosome separation.
ALG8	Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase	Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
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.

Protein-family classification

Druggable: 5 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	2	11.1×	0.036
Enzyme (other)	2	4.8×	0.088
Antibody/Immunoglobulin	1	5.8×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEK8	Kinase	yes		Reg_chr_condens, Prot_kinase_dom, Ser/Thr_kinase_AS
ALG9	Enzyme (other)	yes	2.4.1.259	GPI_mannosylTrfase
NEK9	Kinase	yes		Reg_chr_condens, Prot_kinase_dom, Ser/Thr_kinase_AS
ALG8	Enzyme (other)	yes	2.4.1.265	Glyco_trans_ALG6/ALG8
PKHD1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Pectin_lyase_fold/virulence

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	2
buccal mucosa cell	1
left lobe of thyroid gland	1
body of pancreas	1
endothelial cell	1
ganglionic eminence	1
left ovary	1
right uterine tube	1
tibia	1
left testis	1
right testis	1
testis	1
kidney epithelium	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEK8	196	ubiquitous	marker	buccal mucosa cell, metanephros cortex, left lobe of thyroid gland
ALG9	240	ubiquitous	marker	endothelial cell, body of pancreas, ganglionic eminence
NEK9	296	ubiquitous	marker	tibia, right uterine tube, left ovary
ALG8	282	ubiquitous	marker	right testis, left testis, testis
PKHD1	51	tissue_specific	marker	kidney epithelium, renal medulla, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEK9	2,341
PKHD1	1,211
ALG9	1,167
ALG8	1,010
NEK8	926

Intra-cohort edges

A	B	Sources
ALG8	ALG9	string_interaction
NEK8	NEK9	biogrid_interaction
NEK8	PKHD1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALG9	Q9H6U8	2
NEK9	Q8TD19	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG8	Q9BVK2	92.07
NEK8	Q86SG6	85.23
PKHD1	P08F94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Diseases associated with N-glycosylation of proteins	2	423.0×	1e-04	ALG9, ALG8
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	2	138.4×	6e-04	ALG9, ALG8
Defective ALG9 causes CDG-1l	1	3806.7×	1e-03	ALG9
Defective ALG8 causes CDG-1h	1	3806.7×	1e-03	ALG8
Diseases of glycosylation	2	87.5×	1e-03	ALG9, ALG8
Diseases of metabolism	2	53.6×	0.001	ALG9, ALG8
Asparagine N-linked glycosylation	2	40.1×	0.002	ALG9, ALG8
Activation of NIMA Kinases NEK9, NEK6, NEK7	1	475.8×	0.005	NEK9
Nuclear Envelope Breakdown	1	152.3×	0.014	NEK9
Mitotic Prophase	1	122.8×	0.014	NEK9
Post-translational protein modification	2	12.8×	0.014	ALG9, ALG8
Nuclear Pore Complex (NPC) Disassembly	1	102.9×	0.015	NEK9
Disease	2	8.7×	0.024	ALG9, ALG8
Metabolism of proteins	2	8.2×	0.025	ALG9, ALG8
EML4 and NUDC in mitotic spindle formation	1	30.9×	0.040	NEK9
Mitotic Prometaphase	1	23.1×	0.050	NEK9
M Phase	1	22.0×	0.050	NEK9
Cell Cycle, Mitotic	1	16.1×	0.064	NEK9
Cell Cycle	1	12.0×	0.081	NEK9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dolichol-linked oligosaccharide biosynthetic process	2	337.0×	5e-04	ALG9, ALG8
protein N-linked glycosylation	2	105.3×	0.002	ALG9, ALG8
regulation of cholangiocyte proliferation	1	3370.4×	0.003	PKHD1
regulation of establishment of planar polarity	1	561.7×	0.014	PKHD1
regulation of hippo signaling	1	481.5×	0.014	NEK8
homeostatic process	1	337.0×	0.014	PKHD1
establishment of centrosome localization	1	337.0×	0.014	PKHD1
regulation of cell-matrix adhesion	1	259.3×	0.014	PKHD1
regulation of cell-cell adhesion	1	240.7×	0.014	PKHD1
negative regulation of epithelial cell apoptotic process	1	240.7×	0.014	PKHD1
epithelial cell morphogenesis	1	187.2×	0.015	PKHD1
regulation of TOR signaling	1	187.2×	0.015	PKHD1
regulation of centrosome duplication	1	146.5×	0.017	PKHD1
branching morphogenesis of an epithelial tube	1	146.5×	0.017	PKHD1
obsolete protein N-linked glycosylation via asparagine	1	134.8×	0.017	ALG8
cell-cell junction organization	1	124.8×	0.017	PKHD1
regulation of ERK1 and ERK2 cascade	1	116.2×	0.017	PKHD1
establishment of mitotic spindle orientation	1	96.3×	0.020	PKHD1
obsolete negative regulation of NF-kappaB transcription factor activity	1	71.7×	0.025	PKHD1
regulation of cell adhesion	1	61.3×	0.028	PKHD1
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	52.7×	0.029	PKHD1
determination of left/right symmetry	1	51.1×	0.029	NEK8
positive regulation of epithelial cell proliferation	1	48.9×	0.029	PKHD1
regulation of mitotic cell cycle	1	48.1×	0.029	NEK9
animal organ morphogenesis	1	38.3×	0.035	NEK8
intracellular calcium ion homeostasis	1	29.1×	0.044	PKHD1
kidney development	1	28.1×	0.044	PKHD1
mitotic cell cycle	1	26.8×	0.045	NEK9
cell-cell adhesion	1	20.3×	0.057	PKHD1
heart development	1	15.8×	0.070	NEK8

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
NEK9	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEK9	21	4
NEK8	0	0
ALG9	0	0
ALG8	0	0
PKHD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	NEK9
FEDRATINIB	4	NEK9
DABRAFENIB	4	NEK9
PACRITINIB	4	NEK9
FOSTAMATINIB	4	NEK9
CRIZOTINIB	4	NEK9
DOVITINIB	3	NEK9
LESTAURTINIB	3	NEK9
FORETINIB	2	NEK9
REBASTINIB	2	NEK9
DANUSERTIB	2	NEK9
R-406	2	NEK9
ENMD-2076	2	NEK9
AT-9283	2	NEK9
MILCICLIB	2	NEK9
BMS-754807	2	NEK9
GSK-461364	1	NEK9
KW-2449	1	NEK9
XL-019	1	NEK9
CYC-116	1	NEK9
AST-487	1	NEK9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
NEK9	254	Binding:254
NEK8	37	Binding:37
ALG8	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG9	2.4.1.259, 2.4.1.261	dolichyl-P-Man:Man6GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase, dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase
ALG8	2.4.1.265	dolichyl-P-Glc:Glc1Man9GlcNAc2-PP-dolichol alpha-1,3-glucosyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NEK9	254

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

21 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)
MOMELOTINIB	4	NEK9
FEDRATINIB	4	NEK9
DABRAFENIB	4	NEK9
PACRITINIB	4	NEK9
FOSTAMATINIB	4	NEK9
CRIZOTINIB	4	NEK9
DOVITINIB	3	NEK9
LESTAURTINIB	3	NEK9
FORETINIB	2	NEK9
REBASTINIB	2	NEK9
DANUSERTIB	2	NEK9
R-406	2	NEK9
ENMD-2076	2	NEK9
AT-9283	2	NEK9
MILCICLIB	2	NEK9
BMS-754807	2	NEK9
GSK-461364	1	NEK9
KW-2449	1	NEK9
XL-019	1	NEK9
CYC-116	1	NEK9
AST-487	1	NEK9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NEK9
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALG9
D	Druggable family + AlphaFold only, no drug	3	NEK8, ALG8, PKHD1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NEK8	37	—
ALG9	0	—
ALG8	1	—
PKHD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.