Renal-hepatic-pancreatic dysplasia 2

Summary

Renal-hepatic-pancreatic dysplasia 2 (MONDO:0014174) is a disease caused by NEK8 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NEK8 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 162

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	renal-hepatic-pancreatic dysplasia 2
Mondo ID	MONDO:0014174
OMIM	615415
UMLS	C3809434
MedGen	815764
GARD	0018432
Is cancer (heuristic)	no

Also known as: NEK8 renal-hepatic-pancreatic dysplasia · renal-hepatic-pancreatic dysplasia 2 · renal-hepatic-pancreatic dysplasia caused by mutation in NEK8 · renal-hepatic-pancreatic dysplasia type 2 · RHPD2

Data availability: 162 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › renal-hepatic-pancreatic dysplasia › renal-hepatic-pancreatic dysplasia 2

Related subtypes (1): renal-hepatic-pancreatic dysplasia 1

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

162 retrieved; paginated sample, class counts are floors:

123 uncertain significance, 11 likely pathogenic, 10 likely benign, 6 pathogenic, 6 pathogenic/likely pathogenic, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1177403	NM_178170.3(NEK8):c.515dup (p.Pro172_Glu173insTer)	NEK8	Pathogenic	criteria provided, single submitter
1430306	NM_178170.3(NEK8):c.1359_1360del (p.His454fs)	NEK8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191072	NM_178170.3(NEK8):c.1401G>A (p.Trp467Ter)	NEK8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2885979	NM_178170.3(NEK8):c.1330G>T (p.Glu444Ter)	NEK8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382690	NM_178170.3(NEK8):c.1418-1G>A	NEK8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581785	NM_178170.3(NEK8):c.1495C>T (p.Arg499Ter)	NEK8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
490179	NM_178170.3(NEK8):c.259A>G (p.Thr87Ala)	NEK8	Pathogenic	no assertion criteria provided
490181	NM_178170.3(NEK8):c.1738G>A (p.Gly580Ser)	NEK8	Pathogenic	no assertion criteria provided
490182	NM_178170.3(NEK8):c.47+1G>A	NEK8	Pathogenic	no assertion criteria provided
490183	NM_178170.3(NEK8):c.379C>T (p.Arg127Ter)	NEK8	Pathogenic	criteria provided, multiple submitters, no conflicts
490184	NM_178170.3(NEK8):c.1384C>T (p.Arg462Ter)	NEK8	Pathogenic	criteria provided, single submitter
65408	NM_178170.3(NEK8):c.1795C>T (p.Arg599Ter)	NEK8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581756	NM_178170.3(NEK8):c.763C>T (p.Gln255Ter)	NEK8	Likely pathogenic	criteria provided, single submitter
3581765	NM_178170.3(NEK8):c.995_996del (p.Thr332fs)	NEK8	Likely pathogenic	criteria provided, single submitter
3581767	NM_178170.3(NEK8):c.1068G>A (p.Trp356Ter)	NEK8	Likely pathogenic	criteria provided, single submitter
3581772	NM_178170.3(NEK8):c.1224_1227del	NEK8	Likely pathogenic	criteria provided, single submitter
3581797	NM_178170.3(NEK8):c.1910G>A (p.Trp637Ter)	NEK8	Likely pathogenic	criteria provided, single submitter
3780014	NM_178170.3(NEK8):c.1417+1G>C	NEK8	Likely pathogenic	criteria provided, single submitter
4845749	NM_178170.3(NEK8):c.877_878dup (p.Arg294fs)	NEK8	Likely pathogenic	criteria provided, single submitter
4845887	NM_178170.3(NEK8):c.2066_2073delinsTTTT (p.Pro689fs)	NEK8	Likely pathogenic	criteria provided, single submitter
490177	NM_178170.3(NEK8):c.2076dup (p.Ter693LeuextTer?)	NEK8	Likely pathogenic	criteria provided, single submitter
539140	NM_178170.3(NEK8):c.889+1G>T	NEK8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
974436	NM_178170.3(NEK8):c.322TTC[1] (p.Phe109del)	NEK8	Likely pathogenic	criteria provided, single submitter
1031754	NM_178170.3(NEK8):c.972C>G (p.Pro324=)	NEK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2500285	NM_178170.3(NEK8):c.618G>A (p.Ala206=)	NEK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2266195	NM_178170.3(NEK8):c.1676A>C (p.Asp559Ala)	LOC130060573	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581787	NM_178170.3(NEK8):c.1598C>T (p.Ser533Phe)	LOC130060573	Uncertain significance	criteria provided, multiple submitters, no conflicts
2663928	NM_178170.3(NEK8):c.1891+1G>A	LOC130060574	Uncertain significance	criteria provided, single submitter
3581796	NM_178170.3(NEK8):c.1888G>A (p.Ala630Thr)	LOC130060574	Uncertain significance	criteria provided, single submitter
1004174	NM_178170.3(NEK8):c.2077del (p.Ter693GluextTer?)	NEK8	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 5 · 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
NEK8	Definitive	Autosomal recessive	renal-hepatic-pancreatic dysplasia 2	10
NEK9	Definitive	Autosomal recessive	renal-hepatic-pancreatic dysplasia 2	14

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
NEK9	Orphanet:464366	NEK9-related lethal skeletal dysplasia
NEK9	Orphanet:64754	Nevus comedonicus syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NEK8	HGNC:13387	ENSG00000160602	Q86SG6	Serine/threonine-protein kinase Nek8	gencc,clinvar
NEK9	HGNC:18591	ENSG00000119638	Q8TD19	Serine/threonine-protein kinase Nek9	gencc,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.
NEK9	Serine/threonine-protein kinase Nek9	Pleiotropic regulator of mitotic progression, participating in the control of spindle dynamics and chromosome separation.

Protein-family classification

Druggable: 2 · 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	27.7×	0.001

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEK8	Kinase	yes		Reg_chr_condens, Prot_kinase_dom, Ser/Thr_kinase_AS
NEK9	Kinase	yes		Reg_chr_condens, Prot_kinase_dom, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
left lobe of thyroid gland	1
metanephros cortex	1
left ovary	1
right uterine tube	1
tibia	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
NEK9	296	ubiquitous	marker	tibia, right uterine tube, left ovary

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEK9	2,341
NEK8	926

Intra-cohort edges

A	B	Sources
NEK8	NEK9	biogrid_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NEK9	Q8TD19	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NEK8	Q86SG6	85.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of NIMA Kinases NEK9, NEK6, NEK7	1	1427.5×	0.006	NEK9
Nuclear Envelope Breakdown	1	456.8×	0.007	NEK9
Mitotic Prophase	1	368.4×	0.007	NEK9
Nuclear Pore Complex (NPC) Disassembly	1	308.6×	0.007	NEK9
EML4 and NUDC in mitotic spindle formation	1	92.8×	0.019	NEK9
Mitotic Prometaphase	1	69.2×	0.019	NEK9
M Phase	1	66.0×	0.019	NEK9
Cell Cycle, Mitotic	1	48.2×	0.023	NEK9
Cell Cycle	1	36.0×	0.028	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of hippo signaling	1	1203.7×	0.006	NEK8
determination of left/right symmetry	1	127.7×	0.018	NEK8
regulation of mitotic cell cycle	1	120.4×	0.018	NEK9
animal organ morphogenesis	1	95.8×	0.018	NEK8
mitotic cell cycle	1	66.9×	0.021	NEK9
heart development	1	39.4×	0.029	NEK8
cell division	1	23.1×	0.043	NEK9

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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

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): 0.

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

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

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: 2; 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	0
D	Druggable family + AlphaFold only, no drug	1	NEK8
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NEK8	37	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.