NPHP4

Summary

NPHP4 (nephrocystin 4, HGNC:19104) is a protein-coding gene on chromosome 1p36.31, encoding Nephrocystin-4 (O75161). Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module.

This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 261734 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephronophthisis 4 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,959 total — 75 pathogenic, 67 likely-pathogenic
• Phenotypes (HPO): 28
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_015102

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19104
Approved symbol	NPHP4
Name	nephrocystin 4
Location	1p36.31
Locus type	gene with protein product
Status	Approved
Aliases	SLSN4, KIAA0673, POC10
Ensembl gene	ENSG00000131697
Ensembl biotype	protein_coding
OMIM	607215
Entrez	261734

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 25 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000378156, ENST00000378161, ENST00000378169, ENST00000460696, ENST00000466897, ENST00000468253, ENST00000470763, ENST00000478423, ENST00000489180, ENST00000506941, ENST00000622020, ENST00000892395, ENST00000892396, ENST00000892397, ENST00000892398, ENST00000892399, ENST00000892400, ENST00000892401, ENST00000892402, ENST00000923561, ENST00000923562, ENST00000923563, ENST00000923564, ENST00000923565, ENST00000955266, ENST00000955267, ENST00000955268, ENST00000955269, ENST00000955270, ENST00000955271, ENST00000955272, ENST00000955273, ENST00000955274, ENST00000955275

RefSeq mRNA: 3 — MANE Select: NM_015102 NM_001291593, NM_001291594, NM_015102

CCDS: CCDS44052

Canonical transcript exons

ENST00000378156 — 30 exons

Exon	Start	End
ENSE00001476440	5862811	5863405
ENSE00001476547	5978270	5978413
ENSE00001476550	5992244	5992425
ENSE00001696748	5909152	5909213
ENSE00001720973	5907115	5907222
ENSE00002038847	5986155	5986327
ENSE00003459647	5947104	5947230
ENSE00003470132	5867740	5867896
ENSE00003502281	5874471	5874657
ENSE00003504007	5877093	5877298
ENSE00003523079	5867030	5867115
ENSE00003530979	5905632	5905783
ENSE00003532658	5890868	5891028
ENSE00003535040	5873252	5873335
ENSE00003544137	5904617	5904804
ENSE00003554379	5865102	5865273
ENSE00003566091	5880114	5880239
ENSE00003569388	5969087	5969259
ENSE00003572995	5887286	5887466
ENSE00003578021	5866373	5866458
ENSE00003580853	5927649	5927787
ENSE00003582880	5948070	5948251
ENSE00003583968	5967299	5967363
ENSE00003584153	5933147	5933329
ENSE00003629929	5874874	5875100
ENSE00003630070	5863890	5864033
ENSE00003634229	5905292	5905483
ENSE00003639184	5864338	5864517
ENSE00003675682	5952700	5952836
ENSE00003690356	5961794	5961949

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 89.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1925 / max 82.1518, expressed in 1700 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9973	6.8037	1682
9972	0.3888	212

Top tissues by expression

280 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	89.96	gold quality
adenohypophysis	UBERON:0002196	86.58	gold quality
right lobe of thyroid gland	UBERON:0001119	86.09	gold quality
left lobe of thyroid gland	UBERON:0001120	85.33	gold quality
pituitary gland	UBERON:0000007	83.81	gold quality
right testis	UBERON:0004534	83.15	gold quality
left testis	UBERON:0004533	83.01	gold quality
thyroid gland	UBERON:0002046	82.94	gold quality
skin of abdomen	UBERON:0001416	82.00	gold quality
right frontal lobe	UBERON:0002810	81.61	gold quality
skin of leg	UBERON:0001511	81.03	gold quality
stromal cell of endometrium	CL:0002255	80.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.14	gold quality
tibial nerve	UBERON:0001323	79.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.27	gold quality
testis	UBERON:0000473	79.03	gold quality
ventricular zone	UBERON:0003053	78.86	gold quality
omental fat pad	UBERON:0010414	78.52	gold quality
peritoneum	UBERON:0002358	78.41	gold quality
left ovary	UBERON:0002119	78.35	gold quality
metanephros cortex	UBERON:0010533	78.30	gold quality
anterior cingulate cortex	UBERON:0009835	78.03	gold quality
right ovary	UBERON:0002118	78.02	gold quality
cingulate cortex	UBERON:0003027	77.91	gold quality
right lung	UBERON:0002167	77.74	gold quality
cortical plate	UBERON:0005343	77.71	gold quality
cerebellar hemisphere	UBERON:0002245	77.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.57	gold quality
upper lobe of left lung	UBERON:0008952	77.54	gold quality
cerebellar cortex	UBERON:0002129	77.39	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting NPHP4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-634	97.74	67.11	818
HSA-MIR-8055	97.62	66.09	1023
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-4433A-5P	96.79	65.01	599
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-6863	93.93	67.77	154

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• Encodes a novel protein, nephroretinin, that is conserved in evolution–for example, in the nematode Caenorhabditis elegans. (PMID:12205563)
• Recessive mutations in the NPHP4 gene, encoding the protein nephroretinin, in humans cause nephronophthisis type 4 and Senior-Loken syndrome.There is evolutionary conservation of the NPHP4 gene, with an ortholog in C. elegans. (PMID:12205563)
• Interacts with NPHP1 protein, suggesting that these two proteins participate in a common signaling pathway; identification of five different mutations in unrelated individuals with nephronophthisis (PMID:12244321)
• part of multifunctional complex localized in actin- and microtubule-based structures (PMID:15661758)
• two recessive mutations in NPHP4 are a rare cause of nephronophthisis, and single heterozygous NPHP4 sequence variants are three times more prevalent than two recessive mutations (PMID:15776426)
• retinitis pigmentosa GTPase regulator interacting protein 1 and nephrocystin-4 interact strongly in vitro and in vivo, and that they colocalize in the retina (PMID:16339905)
• the apparent occurrence of an unusual TG 3’ splice site in intron 20 is discussed (PMID:17672918)
• In six families with nephronophthisis, there were two mutations in either NPHP1, NPHP3, or NPHP4, suggesting oligogenicity. (PMID:17855640)
• Two novel homozygous missense sequence variants in exons 18 and 21 were detected in a consanguineous family with nephronophthisis (PMID:17954299)
• These results indicate the novel and independent association between single-point SNP rs1287637 in NPHP4 gene and renal function in non-diabetic Japanese population. (PMID:20844548)
• Identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling. (PMID:21555462)
• NPHP4 mutations are associated with cardiac laterality defects and heterotaxy. (PMID:22550138)
• The ciliary protein nephrocystin-4 translocates the canonical Wnt regulator Jade-1 to the nucleus to negatively regulate beta-catenin signaling. (PMID:22654112)
• homozygous NPHP4 truncating mutation that expands the phenotypic spectrum of NPHP4-related nephronophthisis to also include cerebello-oculo-renal syndrome and abnormal spermatogenesis causing male infertility (PMID:23574405)
• Study provides evidence that KIF13B and NPHP4 are both required for establishment of a specialized caveolin-1 membrane microdomain at the ciliary transition zone, which is essential for Shh-induced accumulation of SMO in the primary cilium as well as for activation of GLI-mediated target gene expression. (PMID:28134340)
• Inherited 3 deleterious mutations in two nephronophthisis genes, NPHP3 and NPHP4 cause unusually severe form of infantile nephronophthisis. (PMID:28392475)
• Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants. (PMID:31810733)
• SENIOR-LOKEN SYNDROME: A Case Series and Review of the Renoretinal Phenotype and Advances of Molecular Diagnosis. (PMID:33512896)
• Association of Nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study. (PMID:34591160)
• A novel NPHP4 homozygous missense variant identified in infertile brothers with multiple morphological abnormalities of the sperm flagella. (PMID:37831349)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nphp4	ENSDARG00000069014
mus_musculus	Nphp4	ENSMUSG00000039577
rattus_norvegicus	Nphp4	ENSRNOG00000011967
caenorhabditis_elegans		WBGENE00011261

Protein

Protein identifiers

Nephrocystin-4 — O75161 (reviewed: O75161)

Alternative names: Nephroretinin

All UniProt accessions (3): D6RA06, O75161, H0YA08

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module. Does not seem to be strictly required for ciliogenesis. Required for building functional cilia. Involved in the organization of the subapical actin network in multiciliated epithelial cells. Seems to recruit INT to basal bodies of motile cilia which subsequently interacts with actin-modifying proteins such as DAAM1. In cooperation with INVS may down-regulate the canonical Wnt pathway and promote the Wnt-PCP pathway by regulating expression and subcellular location of disheveled proteins. Stabilizes protein levels of JADE1 and promotes its translocation to the nucleus leading to cooperative inhibition of canonical Wnt signaling. Acts as a negative regulator of the hippo pathway by association with LATS1 and modifying LATS1-dependent phosphorylation and localization of WWTR1/TAZ.

Subunit / interactions. Interacts with NPHP1. Interacts with NPHP1 and RPGRIP1L/NPHP8; NPHP1, NPHP4 and RPGRIP1L are proposed to form a functional NPHP1-4-8 module localized to cell-cell contacts and the ciliary transition zone; NPHP4 mediates the interaction between NPHP1 and RPGRIP1L. Interacts with IQCB1/NPHP5; the interaction likely requires additional interactors. Interacts with RPGRIP1, CEP164, JADE1, PALS1, INADL, PARD6A, INVS, DVL2, LATS1. Interacts with INTU; INTU mediates the interaction between NPHP4 and DAAM1. Interacts with SPATA7.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium basal body. Microtubule organizing center. Centrosome. Cell junction. Tight junction. Nucleus.

Tissue specificity. Expressed in kidney, skeletal muscle, heart and liver, and to a lesser extent in brain and lung.

Disease relevance. Nephronophthisis 4 (NPHP4) [MIM:606966] An autosomal recessive inherited disease resulting in end-stage renal disease at age ranging between 6 and 35 years. It is a progressive tubulo-interstitial kidney disorder characterized by polydipsia, polyuria, anemia and growth retardation. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. The disease is caused by variants affecting the gene represented in this entry. Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome, including NPHP4, influence the clinical outcome. Senior-Loken syndrome 4 (SLSN4) [MIM:606996] A renal-retinal disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. The disease is caused by variants affecting the gene represented in this entry. May be involved in male infertility. Homozygosity for a frameshift truncating mutation are associated with markedly abnormal sperm morphology. May be involved in cardiac laterality defects and heterotaxy.

Similarity. Belongs to the NPHP4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75161-1	1	yes
O75161-2	2

RefSeq proteins (3): NP_001278522, NP_001278523, NP_055917* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029775	NPHP4	Family
IPR058685	Ig_NPHP4_4th	Domain
IPR058686	Ig_NPHP4_3rd	Domain
IPR058687	Ig_NPHP4_1st	Domain
IPR058688	Ig_NPHP4_2nd	Domain
IPR058764	NPHP4_SK	Domain
IPR058765	NPHP4_C2-like	Domain

Pfam: PF26015, PF26173, PF26186, PF26187, PF26189, PF26190

UniProt features (47 total): sequence variant 37, region of interest 3, splice variant 3, compositionally biased region 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75161-F1	72.44	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 142

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2028269	Signaling by Hippo
R-HSA-5620912	Anchoring of the basal body to the plasma membrane

MSigDB gene sets: 230 (showing top): RNGTGGGC_UNKNOWN, GOBP_BEHAVIOR, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_CELL_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_PHOTORECEPTOR_CELL_MAINTENANCE

GO Biological Process (11): signal transduction (GO:0007165), visual behavior (GO:0007632), actin cytoskeleton organization (GO:0030036), flagellated sperm motility (GO:0030317), photoreceptor cell outer segment organization (GO:0035845), photoreceptor cell maintenance (GO:0045494), retina development in camera-type eye (GO:0060041), negative regulation of canonical Wnt signaling pathway (GO:0090090), cell-cell adhesion (GO:0098609), positive regulation of bicellular tight junction assembly (GO:1903348), protein localization to ciliary transition zone (GO:1904491)

GO Molecular Function (2): structural molecule activity (GO:0005198), protein binding (GO:0005515)

GO Cellular Component (20): nucleoplasm (GO:0005654), centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), nuclear body (GO:0016604), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), ribbon synapse (GO:0097470), ciliary base (GO:0097546), non-motile cilium (GO:0097730), photoreceptor distal connecting cilium (GO:0120206), nucleus (GO:0005634), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), photoreceptor connecting cilium (GO:0032391), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signal Transduction	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cilium	4
microtubule organizing center	3
intracellular membraneless organelle	3
ciliary transition zone	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
behavior	1
response to light stimulus	1
cytoskeleton organization	1
actin filament-based process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
cellular component organization	1
photoreceptor cell development	1
retina homeostasis	1
multicellular organismal process	1
camera-type eye development	1
anatomical structure development	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
cell adhesion	1
bicellular tight junction assembly	1
positive regulation of cell junction assembly	1
regulation of bicellular tight junction assembly	1
protein localization to cilium	1
molecular_function	1
binding	1
nuclear lumen	1
centriole	1
cytoplasm	1
anchoring junction	1
apical junction complex	1
tight junction	1
nucleoplasm	1

Protein interactions and networks

STRING

1394 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPHP4	NPHP1	O15259	999
NPHP4	RPGRIP1L	Q68CZ1	998
NPHP4	RPGRIP1	Q96KN7	992
NPHP4	NPHP3	Q7Z494	984
NPHP4	CEP290	O15078	976
NPHP4	TMEM67	Q5HYA8	967
NPHP4	INVS	Q9Y283	953
NPHP4	IQCB1	Q15051	951
NPHP4	BCAR1	P56945	918
NPHP4	RPGR	Q92834	909
NPHP4	B9D1	Q9UPM9	906
NPHP4	MKS1	Q9NXB0	904
NPHP4	B9D2	Q9BPU9	883
NPHP4	SDCCAG8	Q86SQ7	872
NPHP4	PTK2B	Q14289	869

IntAct

97 interactions, top by confidence:

A	B	Type	Score
NPHP1	NPHP4	psi-mi:“MI:2364”(proximity)	0.930
NPHP4	NPHP1	psi-mi:“MI:0915”(physical association)	0.930
NPHP1	NPHP4	psi-mi:“MI:0915”(physical association)	0.930
NPHP4	NPHP1	psi-mi:“MI:0914”(association)	0.930
NPHP1	NPHP4	psi-mi:“MI:0914”(association)	0.930
RPGRIP1L	NPHP4	psi-mi:“MI:0915”(physical association)	0.760
RPGR	NPHP4	psi-mi:“MI:2364”(proximity)	0.730
RPGR	NPHP4	psi-mi:“MI:0915”(physical association)	0.730
NPHP4	RPGRIP1L	psi-mi:“MI:0915”(physical association)	0.700
RPGRIP1L	NPHP4	psi-mi:“MI:0915”(physical association)	0.700
RPGRIP1L	NPHP4	psi-mi:“MI:0403”(colocalization)	0.700
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
RPGRIP1	NPHP4	psi-mi:“MI:0915”(physical association)	0.620
NPHP4	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.620

BioGRID (88): RPGRIP1 (Affinity Capture-Western), NPHP4 (Affinity Capture-Western), JADE1 (Affinity Capture-Western), NPHP4 (Affinity Capture-MS), NPHP4 (Affinity Capture-MS), NPHP4 (Proximity Label-MS), NPHP4 (Proximity Label-MS), NPHP4 (Proximity Label-MS), AIP (Proximity Label-MS), CACYBP (Proximity Label-MS), HSP90AA1 (Proximity Label-MS), HSP90AB1 (Proximity Label-MS), HSPA1B (Proximity Label-MS), HSPA1L (Proximity Label-MS), HSPA2 (Proximity Label-MS)

ESM2 similar proteins: A1A4V9, A2A8U2, A4IFI1, A8E4X8, B0BMZ6, F1R7R1, G5E8P0, O75161, P12755, P59017, P59240, P85299, P97432, Q14DQ1, Q2HJA5, Q3B7M3, Q3U0L2, Q3ZBK7, Q3ZK22, Q53GS7, Q569K6, Q58DT5, Q5FVG6, Q5RAS2, Q5SNT2, Q5T7N3, Q5XI52, Q60698, Q6NZQ0, Q80U62, Q812A5, Q8C0R7, Q8C190, Q8CC12, Q8IWY9, Q8IYY4, Q8N9B5, Q8NFW9, Q8R1F1, Q8R322

Diamond homologs: B0DOB4, O75161, P59240

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitotic Metaphase and Anaphase	5	13.4×	4e-03
Mitotic Anaphase	5	13.4×	4e-03
RHO GTPases Activate Formins	5	10.8×	5e-03
Separation of Sister Chromatids	6	10.1×	4e-03
M Phase	5	9.2×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
non-motile cilium assembly	5	25.5×	6e-04
mitotic cell cycle	5	11.7×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1959 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	75
Likely pathogenic	67
Uncertain significance	937
Likely benign	549
Benign	82

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068961	NM_015102.5(NPHP4):c.60_61del (p.Arg20fs)	Pathogenic
1069885	NM_015102.5(NPHP4):c.1082_1083dup (p.Tyr362fs)	Pathogenic
1073618	NM_015102.5(NPHP4):c.1271del (p.Lys424fs)	Pathogenic
1323371	NM_015102.5(NPHP4):c.3316-2A>G	Pathogenic
1323372	NM_015102.5(NPHP4):c.669del (p.Glu223fs)	Pathogenic
1323373	NM_015102.5(NPHP4):c.3214C>T (p.Gln1072Ter)	Pathogenic
1376931	NM_015102.5(NPHP4):c.3282G>A (p.Trp1094Ter)	Pathogenic
1387867	NM_015102.5(NPHP4):c.3773_3776del (p.Val1258fs)	Pathogenic
1394852	NM_015102.5(NPHP4):c.3798_3799del (p.His1267fs)	Pathogenic
1411648	NM_015102.5(NPHP4):c.1936C>T (p.Gln646Ter)	Pathogenic
1431545	NM_015102.5(NPHP4):c.685C>T (p.Arg229Ter)	Pathogenic
1453996	NM_015102.5(NPHP4):c.175C>T (p.Arg59Ter)	Pathogenic
1455063	NM_015102.5(NPHP4):c.2611C>T (p.Arg871Ter)	Pathogenic
1458877	NM_015102.5(NPHP4):c.2626C>T (p.Gln876Ter)	Pathogenic
1460374	NC_000001.10:g.(?5933292)(5940319_?)del	Pathogenic
1694483	NM_015102.5(NPHP4):c.3506del (p.Pro1169fs)	Pathogenic
1913817	NM_015102.5(NPHP4):c.257_258del (p.Pro86fs)	Pathogenic
1993877	NM_015102.5(NPHP4):c.477del (p.Arg160fs)	Pathogenic
2001062	NM_015102.5(NPHP4):c.3700C>T (p.Gln1234Ter)	Pathogenic
2021585	NM_015102.5(NPHP4):c.202dup (p.Arg68fs)	Pathogenic
2030835	NM_015102.5(NPHP4):c.2821_2822insT (p.Gln941fs)	Pathogenic
2110331	NM_015102.5(NPHP4):c.1804C>T (p.Gln602Ter)	Pathogenic
2124439	NM_015102.5(NPHP4):c.2773C>T (p.Gln925Ter)	Pathogenic
2202693	NM_015102.5(NPHP4):c.3272dup (p.Ser1092fs)	Pathogenic
2202941	NM_015102.5(NPHP4):c.3196C>T (p.Gln1066Ter)	Pathogenic
2426064	NC_000001.10:g.(?5950908)(5951108_?)del	Pathogenic
2426065	NC_000001.10:g.(?5964657)(5969293_?)del	Pathogenic
2577458	NM_015102.5(NPHP4):c.1336C>T (p.Gln446Ter)	Pathogenic
2632247	NM_015102.5(NPHP4):c.2932del (p.Glu978fs)	Pathogenic
2681745	NM_015102.5(NPHP4):c.4237_4249del (p.Asp1413fs)	Pathogenic

SpliceAI

7624 predictions. Top by Δscore:

Variant	Effect	Δscore
1:5863900:T:TA	donor_gain	1.0000
1:5864029:AAGGC:A	acceptor_gain	1.0000
1:5864030:AGGC:A	acceptor_gain	1.0000
1:5864031:GGC:G	acceptor_gain	1.0000
1:5864032:GC:G	acceptor_gain	1.0000
1:5864033:CC:C	acceptor_gain	1.0000
1:5864034:C:CC	acceptor_gain	1.0000
1:5864034:CT:C	acceptor_loss	1.0000
1:5864036:G:C	acceptor_gain	1.0000
1:5864333:CAGA:C	donor_gain	1.0000
1:5864337:C:CA	donor_loss	1.0000
1:5864514:CTGT:C	acceptor_gain	1.0000
1:5864518:C:CC	acceptor_gain	1.0000
1:5864521:C:CT	acceptor_gain	1.0000
1:5864522:A:T	acceptor_gain	1.0000
1:5865099:TAC:T	donor_loss	1.0000
1:5865100:ACC:A	donor_loss	1.0000
1:5865140:T:A	donor_gain	1.0000
1:5866371:A:AC	donor_gain	1.0000
1:5866372:C:CC	donor_gain	1.0000
1:5873333:GGCCT:G	acceptor_loss	1.0000
1:5873334:GCC:G	acceptor_loss	1.0000
1:5873335:CCTGC:C	acceptor_loss	1.0000
1:5873336:C:CC	acceptor_gain	1.0000
1:5873336:C:G	acceptor_loss	1.0000
1:5873337:T:G	acceptor_loss	1.0000
1:5874868:CCTCA:C	donor_loss	1.0000
1:5874870:TCA:T	donor_loss	1.0000
1:5874871:CAC:C	donor_loss	1.0000
1:5874872:ACCTG:A	donor_loss	1.0000

AlphaMissense

9249 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:5863968:G:C	N1354K	0.996
1:5863968:G:T	N1354K	0.996
1:5864028:A:C	F1334L	0.995
1:5864028:A:T	F1334L	0.995
1:5864030:A:G	F1334L	0.995
1:5863976:A:C	Y1352D	0.994
1:5905307:A:G	F647S	0.994
1:5874927:G:C	N997K	0.993
1:5874927:G:T	N997K	0.993
1:5887457:G:T	R772S	0.993
1:5866385:A:T	V1211D	0.992
1:5866426:C:A	K1197N	0.992
1:5866426:C:G	K1197N	0.992
1:5867889:A:G	F1108S	0.992
1:5890890:C:T	G761E	0.992
1:5890918:A:G	W752R	0.992
1:5890918:A:T	W752R	0.992
1:5948202:A:G	L287P	0.992
1:5863981:A:G	I1350T	0.991
1:5948205:C:G	R286P	0.991
1:5969149:A:C	F130L	0.991
1:5969149:A:T	F130L	0.991
1:5969151:A:G	F130L	0.991
1:5865242:A:G	W1226R	0.990
1:5865242:A:T	W1226R	0.990
1:5866430:A:G	L1196P	0.990
1:5867063:G:C	S1175R	0.990
1:5867063:G:T	S1175R	0.990
1:5867065:T:G	S1175R	0.990
1:5874939:A:C	F993L	0.990

dbSNP variants (sampled 300 via entrez): RS1000019758 (1:5909020 C>T), RS1000029735 (1:5885496 G>T), RS1000034983 (1:5885732 C>G), RS1000043227 (1:5986560 T>A), RS1000057008 (1:5909775 C>T), RS1000107985 (1:5907500 A>G), RS1000110178 (1:5979331 TGGGGC>T,TGGGGCGGGGC), RS1000123094 (1:5914298 G>T), RS1000128930 (1:5920675 T>C), RS1000130263 (1:5950409 G>A,T), RS1000137614 (1:5990396 G>C), RS1000144425 (1:5979020 C>A), RS1000153412 (1:5956943 C>G), RS1000157936 (1:5874405 G>A,C), RS1000183691 (1:5946069 C>A)

Disease associations

OMIM: gene MIM:607215 | disease phenotypes: MIM:256100, MIM:606966, MIM:606996, MIM:268000, MIM:204000, MIM:209900, MIM:120435, MIM:266900, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
nephronophthisis 4	Definitive	Autosomal recessive
Senior-Loken syndrome 4	Definitive	Autosomal recessive
Senior-Loken syndrome	Supportive	Autosomal recessive
nephronophthisis 1	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nephronophthisis 4	Definitive	AR

Mondo (19): nephronophthisis (MONDO:0019005), nephronophthisis 4 (MONDO:0011752), Senior-Loken syndrome 4 (MONDO:0011756), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), ciliopathy (MONDO:0005308), kidney disorder (MONDO:0005240), Leber congenital amaurosis (MONDO:0018998), cholestasis (MONDO:0001751), focal segmental glomerulosclerosis (MONDO:0100313), Bardet-Biedl syndrome (MONDO:0015229), atypical hemolytic-uremic syndrome (MONDO:0016244), Lynch syndrome 1 (MONDO:0007356), optic atrophy (MONDO:0003608), infertility disorder (MONDO:0005047)

Orphanet (11): Nephronophthisis (Orphanet:655), Senior-Loken syndrome (Orphanet:3156), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), Ciliopathy (Orphanet:363250), Leber congenital amaurosis (Orphanet:65), Bardet-Biedl syndrome (Orphanet:110), Atypical hemolytic uremic syndrome (Orphanet:2134), Lynch syndrome (Orphanet:144), CHARGE syndrome (Orphanet:138), Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000090	Nephronophthisis
HP:0000092	Renal tubular atrophy
HP:0000103	Polyuria
HP:0000108	Renal corticomedullary cysts
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000556	Retinal dystrophy
HP:0000646	Amblyopia
HP:0000822	Hypertension
HP:0001141	Severely reduced visual acuity
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001510	Growth delay
HP:0001583	Rotary nystagmus
HP:0001903	Anemia
HP:0001959	Polydipsia
HP:0002612	Congenital hepatic fibrosis
HP:0003774	Stage 5 chronic kidney disease
HP:0004322	Short stature
HP:0004348	Abnormality of bone mineral density
HP:0005576	Tubulointerstitial fibrosis
HP:0007703	Abnormal retinal pigmentation
HP:0008209	Premature ovarian insufficiency
HP:0010579	Cone-shaped epiphysis
HP:0012622	Chronic kidney disease

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000363_5	QT interval	1.000000e-16
GCST001694_1	Response to taxane treatment (paclitaxel)	5.000000e-07
GCST005757_2	Dimensional psychopathology (Positive)	4.000000e-07
GCST010397_63	Gut microbiota (bacterial taxa, rank normal transformation method)	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0009097	positive domain measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (17)

Descriptor	Name	Tree numbers
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D058747	CHARGE Syndrome	C09.218.458.341.186.500.250; C10.597.751.418.341.186.500.250; C10.597.751.941.162.625.250; C11.270.147.500; C11.966.075.375.250; C16.131.077.299.250; C16.320.165; C23.888.592.763.393.341.186.500.500; C23.888.592.763.941.162.625.500
D002779	Cholestasis	C06.130.120.135
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007246	Infertility	C12.100.750
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C566906	Cakut (supp.)
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)
C564640	Nephronophthisis 4 (supp.)
C537699	Nephronophthisis, familial juvenile (supp.)
C537580	Senior Loken Syndrome (supp.)
C537581	Senior-Loken syndrome 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
mercuric bromide	decreases expression, affects cotreatment	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases reaction, affects binding	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Acrylamide	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1

Clinical trials (associated diseases)

265 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)