Nephronophthisis 4

Summary

Nephronophthisis 4 (MONDO:0011752) is a disease caused by NPHP4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NPHP4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 607

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephronophthisis 4
Mondo ID	MONDO:0011752
MeSH	C564640
OMIM	606966
DOID	DOID:0111115
SNOMED CT	446989009
UMLS	C1847013
MedGen	339667
GARD	0024821
Is cancer (heuristic)	no

Also known as: nephronophthisis (disease) caused by mutation in NPHP4 · nephronophthisis 4 · nephronophthisis type 4 · NPHP4 · NPHP4 nephronophthisis (disease)

Data availability: 607 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 › autosomal genetic disease › autosomal recessive disease › nephronophthisis › nephronophthisis 4

Related subtypes (17): nephronophthisis 1, nephronophthisis 2, nephronophthisis 3, nephronophthisis 7, nephronophthisis-like nephropathy 1, nephronophthisis 11, nephronophthisis 12, nephronophthisis 9, nephronophthisis 13, nephronophthisis 14, nephronophthisis 15, nephronophthisis 16, nephronophthisis 18, nephronophthisis 19, nephronophthisis 20, late-onset nephronophthisis, nephronophthisis-like nephropathy 2

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:

363 uncertain significance, 85 conflicting classifications of pathogenicity, 30 likely pathogenic, 29 likely benign, 27 benign/likely benign, 23 pathogenic/likely pathogenic, 23 pathogenic, 20 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2657	NM_198428.3(BBS9):c.1792C>T (p.Arg598Ter)	BBS9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068634	NM_015102.5(NPHP4):c.3083del (p.Gly1028fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072607	NM_015102.5(NPHP4):c.2908dup (p.Leu970fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073618	NM_015102.5(NPHP4):c.1271del (p.Lys424fs)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
1179132	NM_015102.5(NPHP4):c.3644+1G>T	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1382268	NM_015102.5(NPHP4):c.3458G>A (p.Trp1153Ter)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387867	NM_015102.5(NPHP4):c.3773_3776del (p.Val1258fs)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
1388969	NM_015102.5(NPHP4):c.3368_3369del (p.Val1123fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1433031	NM_015102.5(NPHP4):c.2007del (p.Phe670fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2156394	NM_015102.5(NPHP4):c.3418G>T (p.Glu1140Ter)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577458	NM_015102.5(NPHP4):c.1336C>T (p.Gln446Ter)	NPHP4	Pathogenic	no assertion criteria provided
2681745	NM_015102.5(NPHP4):c.4237_4249del (p.Asp1413fs)	NPHP4	Pathogenic	criteria provided, single submitter
2719506	NM_015102.5(NPHP4):c.3148del (p.Gln1050fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2872668	NM_015102.5(NPHP4):c.1692_1704del (p.Ala565fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066276	NM_015102.5(NPHP4):c.793C>T (p.Gln265Ter)	NPHP4	Pathogenic	criteria provided, single submitter
3391158	NM_015102.5(NPHP4):c.2635A>T (p.Lys879Ter)	NPHP4	Pathogenic	criteria provided, single submitter
3399	NM_015102.5(NPHP4):c.2368G>T (p.Glu790Ter)	NPHP4	Pathogenic	criteria provided, single submitter
3400	NM_015102.5(NPHP4):c.2377C>T (p.Gln793Ter)	NPHP4	Pathogenic	criteria provided, single submitter
3401	NM_015102.5(NPHP4):c.2044C>T (p.Arg682Ter)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
3402	NM_015102.5(NPHP4):c.2972T>C (p.Phe991Ser)	NPHP4	Pathogenic	no assertion criteria provided
3403	NM_015102.5(NPHP4):c.3272del (p.Val1091fs)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
3405	NM_015102.5(NPHP4):c.1972C>T (p.Arg658Ter)	NPHP4	Pathogenic	criteria provided, single submitter
3586786	NM_015102.5(NPHP4):c.1843C>T (p.Gln615Ter)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587242	NM_015102.5(NPHP4):c.111G>A (p.Trp37Ter)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
3900025	NM_015102.5(NPHP4):c.641del (p.Ile214fs)	NPHP4	Pathogenic	criteria provided, single submitter
4531512	NM_015102.5(NPHP4):c.4024G>T (p.Glu1342Ter)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
498434	NM_015102.5(NPHP4):c.2011C>T (p.Gln671Ter)	NPHP4	Pathogenic	criteria provided, multiple submitters, no conflicts
501697	NM_015102.5(NPHP4):c.189_192del (p.Phe63fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
503803	NM_015102.5(NPHP4):c.1421_1423delinsCGTGG (p.Lys474fs)	NPHP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
562343	NM_015102.5(NPHP4):c.1149_1150insCC (p.Ala384fs)	NPHP4	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
NPHP4	Definitive	Autosomal recessive	nephronophthisis 4	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPHP4	Orphanet:3156	Senior-Loken syndrome
NPHP4	Orphanet:93592	Juvenile nephronophthisis
BBS9	Orphanet:110	Bardet-Biedl 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
NPHP4	HGNC:19104	ENSG00000131697	O75161	Nephrocystin-4	gencc,clinvar
BBS9	HGNC:30000	ENSG00000122507	Q3SYG4	Protein PTHB1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPHP4	Nephrocystin-4	Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module.
BBS9	Protein PTHB1	The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPHP4	Other/Unknown	no		NPHP4, Ig_NPHP4_4th, Ig_NPHP4_3rd
BBS9	Other/Unknown	no		PTHB1, PHTB1_N_dom, PHTB1_GAE_dom

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
adenohypophysis	1
right lobe of thyroid gland	1
right uterine tube	1
calcaneal tendon	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPHP4	165	ubiquitous	marker	right uterine tube, adenohypophysis, right lobe of thyroid gland
BBS9	279	ubiquitous	marker	oocyte, secondary oocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPHP4	1,579
BBS9	132

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BBS9	Q3SYG4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NPHP4	O75161	72.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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 Hippo	1	271.9×	0.006	NPHP4
BBSome-mediated cargo-targeting to cilium	1	248.3×	0.006	BBS9
Anchoring of the basal body to the plasma membrane	1	56.5×	0.018	NPHP4

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
visual behavior	1	1404.3×	0.006	NPHP4
protein localization to ciliary transition zone	1	1203.7×	0.006	NPHP4
positive regulation of bicellular tight junction assembly	1	842.6×	0.006	NPHP4
photoreceptor cell outer segment organization	1	526.6×	0.008	NPHP4
protein localization to cilium	1	200.6×	0.015	BBS9
photoreceptor cell maintenance	1	179.3×	0.015	NPHP4
retina development in camera-type eye	1	127.7×	0.018	NPHP4
fat cell differentiation	1	90.6×	0.022	BBS9
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.027	NPHP4
flagellated sperm motility	1	58.5×	0.027	NPHP4
cell-cell adhesion	1	50.8×	0.029	NPHP4
visual perception	1	39.8×	0.031	BBS9
actin cytoskeleton organization	1	39.6×	0.031	NPHP4
cilium assembly	1	36.8×	0.031	BBS9
protein transport	1	21.9×	0.048	BBS9
signal transduction	1	8.0×	0.121	NPHP4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPHP4	0	0
BBS9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
E	Difficult family or no structure, no drug	2	NPHP4, BBS9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NPHP4	0	—
BBS9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.