Nephronophthisis 3

Summary

Nephronophthisis 3 (MONDO:0011456) is a disease caused by NPHP3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: NPHP3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 399

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephronophthisis 3
Mondo ID	MONDO:0011456
MeSH	C565780
OMIM	604387
DOID	DOID:0111114
UMLS	C1858392
MedGen	346809
GARD	0018179
Is cancer (heuristic)	no

Also known as: nephronophthisis (disease) caused by mutation in NPHP3 · nephronophthisis 3 · nephronophthisis type 3 · NPH3 · NPHP3 · NPHP3 nephronophthisis (disease)

Data availability: 399 ClinVar variants · 2 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 3

Related subtypes (17): nephronophthisis 1, nephronophthisis 2, nephronophthisis 4, 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

399 retrieved; paginated sample, class counts are floors:

230 uncertain significance, 64 conflicting classifications of pathogenicity, 28 likely benign, 21 pathogenic, 19 pathogenic/likely pathogenic, 19 likely pathogenic, 15 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069581	NM_153240.5(NPHP3):c.3402_3403del (p.Ala1135fs)	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
1454636	NM_153240.5(NPHP3):c.469del (p.Arg157fs)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195423	NM_153240.5(NPHP3):c.434_437del (p.Glu145fs)	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
2019407	NM_153240.5(NPHP3):c.1289C>G (p.Ser430Ter)	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
2021418	NM_153240.5(NPHP3):c.1675del (p.His559fs)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
220868	NM_153240.5(NPHP3):c.2694-2_2694-1del	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2632	NM_153240.5(NPHP3):c.3821GAG[1] (p.Gly1275del)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2634	NM_153240.5(NPHP3):c.1381G>T (p.Glu461Ter)	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
2638	NM_153240.5(NPHP3):c.3340C>T (p.Gln1114Ter)	NPHP3	Pathogenic	criteria provided, single submitter
2640	NM_153240.5(NPHP3):c.2104C>T (p.Arg702Ter)	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
3383107	NM_153240.5(NPHP3):c.3357_3379dup (p.Leu1127delinsProTer)	NPHP3	Pathogenic	criteria provided, single submitter
403710	NM_153240.5(NPHP3):c.3608del (p.Ala1203fs)	NPHP3	Pathogenic	criteria provided, single submitter
4280324	NM_153240.5(NPHP3):c.2571_2574del	NPHP3	Pathogenic	criteria provided, single submitter
430726	NM_153240.5(NPHP3):c.424C>T (p.Arg142Ter)	NPHP3	Pathogenic	criteria provided, single submitter
462725	NM_153240.5(NPHP3):c.1985+1G>A	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
571434	NM_153240.5(NPHP3):c.2956dup (p.Gln986fs)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
659899	NM_153240.5(NPHP3):c.1087_1090del (p.Val363fs)	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
800889	NM_153240.5(NPHP3):c.3406C>T (p.Gln1136Ter)	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
812666	NM_153240.5(NPHP3):c.520-1G>T	NPHP3	Pathogenic	criteria provided, multiple submitters, no conflicts
936828	NM_153240.5(NPHP3):c.2851C>T (p.Arg951Ter)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96511	NM_153240.5(NPHP3):c.2369T>C (p.Leu790Pro)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
974439	NM_153240.5(NPHP3):c.1943dup (p.Ile649fs)	NPHP3	Pathogenic	criteria provided, single submitter
996537	NM_153240.5(NPHP3):c.2805C>T (p.Gly935=)	NPHP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029229	NM_153240.5(NPHP3):c.2570+1G>T	NPHP3-ACAD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454640	NM_153240.5(NPHP3):c.3775C>T (p.Arg1259Ter)	NPHP3-ACAD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216136	NM_153240.5(NPHP3):c.1817G>A (p.Trp606Ter)	NPHP3-ACAD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2633	NM_153240.5(NPHP3):c.1079G>C (p.Ser360Thr)	NPHP3-ACAD11	Pathogenic	no assertion criteria provided
2634638	NM_153240.5(NPHP3):c.3812+2dup	NPHP3-ACAD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2681759	NM_153240.5(NPHP3):c.748C>T (p.Gln250Ter)	NPHP3-ACAD11	Pathogenic	criteria provided, multiple submitters, no conflicts
499565	NM_153240.5(NPHP3):c.2311-2A>G	NPHP3-ACAD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
NPHP3	Definitive	Autosomal recessive	nephronophthisis	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPHP3	Orphanet:294415	Renal-hepatic-pancreatic dysplasia
NPHP3	Orphanet:3032	NPHP3-related Meckel-like syndrome
NPHP3	Orphanet:3156	Senior-Loken syndrome
NPHP3	Orphanet:93589	Late-onset nephronophthisis
NPHP3	Orphanet:93591	Infantile nephronophthisis

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPHP3	HGNC:7907	ENSG00000113971	Q7Z494	Nephrocystin-3	gencc,clinvar
NPHP3-AS1	HGNC:24129	ENSG00000248724		NPHP3 antisense RNA 1	clinvar
NPHP3-ACAD11	HGNC:48351	ENSG00000274810		NPHP3-ACAD11 readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPHP3	Nephrocystin-3	Required for normal ciliary development and function.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPHP3	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, P-loop_NTPase
NPHP3-AS1	Other/Unknown	no
NPHP3-ACAD11	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
layer of synovial tissue	1
left ovary	1
superficial temporal artery	1
secondary oocyte	1
sural nerve	1
calcaneal tendon	1
endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPHP3	254	ubiquitous	marker	superficial temporal artery, layer of synovial tissue, left ovary
NPHP3-AS1	59		marker	sural nerve, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
NPHP3-ACAD11	133	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPHP3	2,275
NPHP3-AS1	0
NPHP3-ACAD11	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPHP3	Q7Z494	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
Trafficking of myristoylated proteins to the cilium	1	2284.0×	4e-04	NPHP3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
determination of intestine left/right asymmetry	1	16852.0×	7e-04	NPHP3
determination of stomach left/right asymmetry	1	16852.0×	7e-04	NPHP3
convergent extension involved in gastrulation	1	8426.0×	9e-04	NPHP3
convergent extension	1	5617.3×	9e-04	NPHP3
determination of pancreatic left/right asymmetry	1	3370.4×	9e-04	NPHP3
maintenance of animal organ identity	1	3370.4×	9e-04	NPHP3
regulation of Wnt signaling pathway, planar cell polarity pathway	1	3370.4×	9e-04	NPHP3
determination of liver left/right asymmetry	1	2808.7×	9e-04	NPHP3
ureter development	1	2808.7×	9e-04	NPHP3
atrial septum development	1	2106.5×	0.001	NPHP3
kidney morphogenesis	1	1872.4×	0.001	NPHP3
epithelial cilium movement involved in determination of left/right asymmetry	1	1296.3×	0.002	NPHP3
establishment or maintenance of cell polarity	1	401.2×	0.005	NPHP3
photoreceptor cell maintenance	1	358.6×	0.005	NPHP3
non-motile cilium assembly	1	290.6×	0.006	NPHP3
heart looping	1	267.5×	0.006	NPHP3
determination of left/right symmetry	1	255.3×	0.006	NPHP3
lung development	1	198.3×	0.007	NPHP3
kidney development	1	140.4×	0.009	NPHP3
extracellular matrix organization	1	122.1×	0.010	NPHP3
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.010	NPHP3
Wnt signaling pathway	1	99.7×	0.011	NPHP3
lipid metabolic process	1	91.6×	0.011	NPHP3
cilium assembly	1	73.6×	0.014	NPHP3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
NPHP3	0	0
NPHP3-AS1	0	0
NPHP3-ACAD11	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	3	NPHP3, NPHP3-AS1, NPHP3-ACAD11

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)
NPHP3	0	—
NPHP3-AS1	0	—
NPHP3-ACAD11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.