INVS

Summary

INVS (inversin, HGNC:17870) is a protein-coding gene on chromosome 9q31.1, encoding Inversin (Q9Y283). Required for normal renal development and establishment of left-right axis.

This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 27130 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephronophthisis 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 1,156 total — 83 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 31
• MANE Select transcript: NM_014425

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17870
Approved symbol	INVS
Name	inversin
Location	9q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000119509
Ensembl biotype	protein_coding
OMIM	243305
Entrez	27130

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000262456, ENST00000262457, ENST00000374921, ENST00000460636, ENST00000466647, ENST00000480309, ENST00000496467, ENST00000885857, ENST00000885858, ENST00000885859, ENST00000951904, ENST00000951905

RefSeq mRNA: 3 — MANE Select: NM_014425 NM_001318381, NM_001318382, NM_014425

CCDS: CCDS6746

Canonical transcript exons

ENST00000262457 — 17 exons

Exon	Start	End
ENSE00000805775	100296917	100297146
ENSE00000805778	100297936	100298010
ENSE00000983253	100242570	100242679
ENSE00000983254	100246616	100246787
ENSE00000983255	100252283	100252438
ENSE00000983256	100252907	100253136
ENSE00000983257	100264822	100264928
ENSE00000983258	100272864	100273076
ENSE00000983259	100284320	100284603
ENSE00001022908	100292326	100293043
ENSE00001090713	100240060	100240240
ENSE00001148623	100099243	100099416
ENSE00001163496	100300568	100302175
ENSE00003538446	100226062	100226235
ENSE00003547152	100126383	100126549
ENSE00003568210	100229660	100229827
ENSE00003654542	100104498	100104627

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 87.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2175 / max 224.5924, expressed in 1800 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97705	12.8764	1800
97704	0.3411	171

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	87.33	gold quality
adrenal tissue	UBERON:0018303	87.16	gold quality
sural nerve	UBERON:0015488	85.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.77	gold quality
pancreatic ductal cell	CL:0002079	82.63	gold quality
sperm	CL:0000019	81.84	silver quality
left ovary	UBERON:0002119	81.03	gold quality
right lobe of liver	UBERON:0001114	81.02	gold quality
ventricular zone	UBERON:0003053	81.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.96	gold quality
tendon	UBERON:0000043	80.91	gold quality
stromal cell of endometrium	CL:0002255	80.81	gold quality
islet of Langerhans	UBERON:0000006	80.64	gold quality
right ovary	UBERON:0002118	80.29	gold quality
male germ cell	CL:0000015	80.05	silver quality
colonic epithelium	UBERON:0000397	79.97	gold quality
body of uterus	UBERON:0009853	79.27	gold quality
adrenal gland	UBERON:0002369	79.21	gold quality
right adrenal gland	UBERON:0001233	79.17	gold quality
right adrenal gland cortex	UBERON:0035827	79.10	gold quality
left adrenal gland	UBERON:0001234	79.07	gold quality
ganglionic eminence	UBERON:0004023	79.06	gold quality
left adrenal gland cortex	UBERON:0035825	78.83	gold quality
tibial nerve	UBERON:0001323	78.58	gold quality
endocervix	UBERON:0000458	78.45	gold quality
popliteal artery	UBERON:0002250	78.42	gold quality
ectocervix	UBERON:0012249	78.42	gold quality
tibial artery	UBERON:0007610	78.40	gold quality
left coronary artery	UBERON:0001626	78.22	gold quality
aorta	UBERON:0000947	77.97	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EP300, KAT2B

miRNA regulators (miRDB)

73 targeting INVS, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-190A-5P	99.54	71.45	933

Literature-anchored findings (GeneRIF, showing 14)

• has conserved ankyrin repeat and IQ domains and interacts with calmodulin (PMID:11941489)
• analysis of a homozygous mutation in exon 13 of inversin (INVS) (C2719T, R907X) in a patient with retinitis pigmentosa and renal failure [case report] (PMID:16522655)
• Thus, although considered a common variant, inv(10)(p11.2q21.2) has a single ancestral founder among northern Europeans. (PMID:16642442)
• new mutant genes might be responsible for the early onset of ESRD in infantile NPHP with features of JBTS (PMID:17216245)
• Cystic kidney disease has been linked to mutations in the Invs gene in mice with an inversion of embryonic turning (inv/inv) and the INVS (NPHP2) gene in human infantile nephronophthisis (NPH). (PMID:18218308)
• screened 43 families with infantile nephronophthisis (ESRD less than 5 years of age) for NPHP2 and NPHP3 mutations and determined genotype-phenotype correlations (PMID:19177160)
• INVS mutation can cause juvenile nephronophthisis with abnormal reactivity of the Wnt/beta-catenin pathway. (PMID:20798123)
• Truncating mutations in NPHP2 gene is associated with nephronophthisis-related ciliopathy. (PMID:23559409)
• ANKS6 as a new NPHP family member that assembles a distinct module of nephronophthisis-associated proteins, encompassing NEK8, INVS and NPHP3. (PMID:23793029)
• Akt phosphorylates inversin at amino acids 864-866 that are required not only for Akt interaction, but also for inversin dimerization. (PMID:27220846)
• Collectively, these results indicated that inversin might promote the tumorigenicity of lung cancer cells and serve as a novel therapeutic target of non-small cell lung cancer. (PMID:28618971)
• Inversin required for ciliary translocation of Smo and activation of the Shh pathway; Shh signaling promotes inversin phosphorylation by PKA and inversin-Smo interaction (PMID:30598432)
• Novel fibrillar structure in the inversin compartment of primary cilia revealed by 3D single-molecule superresolution microscopy. (PMID:31895004)
• fetus diagnosed with type II nephronophthisis had a heterozygous c.100+1G>A variant and deletion of exon 3 of the INVS gene (PMID:32335886)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	invs	ENSDARG00000002213
mus_musculus	Invs	ENSMUSG00000028344
rattus_norvegicus	Invs	ENSRNOG00000008632
caenorhabditis_elegans		WBGENE00013835

Protein

Protein identifiers

Inversin — Q9Y283 (reviewed: Q9Y283)

Alternative names: Inversion of embryo turning homolog, Nephrocystin-2

All UniProt accessions (1): Q9Y283

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal renal development and establishment of left-right axis. Probably acts as a molecular switch between different Wnt signaling pathways. Inhibits the canonical Wnt pathway by targeting cytoplasmic disheveled (DVL1) for degradation by the ubiquitin-proteasome. This suggests that it is required in renal development to oppose the repression of terminal differentiation of tubular epithelial cells by Wnt signaling. Involved in the organization of apical junctions in kidney cells together with NPHP1, NPHP4 and RPGRIP1L/NPHP8. Does not seem to be strictly required for ciliogenesis.

Subunit / interactions. Binds calmodulin via its IQ domains. Interacts with APC2. Interacts with alpha-, beta-, and gamma-catenin. Interacts with N-cadherin (CDH2). Interacts with microtubules. Interacts with NPHP1. Interacts with DVL1, PRICKLE (PRICKLE1 or PRICKLE2) and Strabismus (VANGL1 or VANGL2). Interacts with IQCB1; the interaction likely requires additional interactors. Component of a complex containing at least ANKS6, INVS, NEK8 and NPHP3. ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary axoneme.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle. Membrane. Nucleus. Cell projection. Cilium.

Tissue specificity. Widely expressed. Strongly expressed in the primary cilia of renal tubular cells.

Post-translational modifications. May be ubiquitinated via its interaction with APC2. Hydroxylated at Asn-75, most probably by HIF1AN.

Disease relevance. Nephronophthisis 2 (NPHP2) [MIM:602088] An autosomal recessive disorder resulting in end-stage renal disease. It is characterized by early onset and rapid progression. Phenotypic manifestations include enlarged kidneys, chronic tubulo-interstitial nephritis, anemia, hyperkalemic metabolic acidosis. Some patients also display situs inversus. Pathologically, it differs from later-onset nephronophthisis by the absence of medullary cysts and thickened tubular basement membranes, and by the presence of cortical microcysts. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The D-box 1 (destruction box 1) mediates the interaction with APC2, and may act as a recognition signal for degradation via the ubiquitin-proteasome pathway.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y283-1	1	yes
Q9Y283-2	2, S2
Q9Y283-3	3

RefSeq proteins (3): NP_001305310, NP_001305311, NP_055240* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF00612, PF12796

UniProt features (45 total): repeat 16, compositionally biased region 10, sequence variant 4, region of interest 3, splice variant 3, domain 2, short sequence motif 2, modified residue 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y283-F1	70.76	0.49

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 (2): 75, 661

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 234 (showing top): RRAGTTGT_UNKNOWN, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, AACYNNNNTTCCS_UNKNOWN, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, AACWWCAANK_UNKNOWN, COUP_01, MYOD_01, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_LOBULAR_NORMAL_DN, MYOD_Q6, MORF_BMPR2, TATA_C, AACTTT_UNKNOWN, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (4): kidney development (GO:0001822), Wnt signaling pathway (GO:0016055), negative regulation of canonical Wnt signaling pathway (GO:0090090), protein localization to ciliary inversin compartment (GO:1904108)

GO Molecular Function (2): calmodulin binding (GO:0005516), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), spindle (GO:0005819), microtubule (GO:0005874), cilium (GO:0005929), membrane (GO:0016020), cytoskeleton (GO:0005856), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
microtubule cytoskeleton	2
intracellular membraneless organelle	2
animal organ development	1
renal system development	1
cell surface receptor signaling pathway	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
protein localization to cilium	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
polymeric cytoskeletal fiber	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

2050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INVS	DVL1	O14640	990
INVS	NPHP3	Q7Z494	973
INVS	NPHP4	O75161	953
INVS	NPHP1	O15259	950
INVS	NEK8	Q86SG6	946
INVS	NEK9	Q8TD19	928
INVS	ANKS6	Q68DC2	860
INVS	AHI1	Q8N157	807
INVS	IQCB1	Q15051	784
INVS	CALML3	P27482	772
INVS	CEP290	O15078	770
INVS	CALM1	P02593	770
INVS	CALML5	Q9NZT1	770
INVS	CALML6	Q8TD86	764
INVS	CALML4	Q96GE6	764

IntAct

23 interactions, top by confidence:

A	B	Type	Score
INVS	HIF1AN	psi-mi:“MI:0915”(physical association)	0.640
INVS	B9D2	psi-mi:“MI:0407”(direct interaction)	0.590
INVS	B9D2	psi-mi:“MI:0915”(physical association)	0.590
B9D2	INVS	psi-mi:“MI:0915”(physical association)	0.590
CALM1	INVS	psi-mi:“MI:0915”(physical association)	0.550
RUVBL1	INVS	psi-mi:“MI:0915”(physical association)	0.400
INVS	DDB1	psi-mi:“MI:0915”(physical association)	0.400
INVS	IFT70B	psi-mi:“MI:0915”(physical association)	0.400
INVS	ZNF512B	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
LMTK2	HAL	psi-mi:“MI:0914”(association)	0.350
TRIM52	MEIOC	psi-mi:“MI:0914”(association)	0.350
EXT2	EXTL3	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
NPHP4	AIP	psi-mi:“MI:2364”(proximity)	0.270
NPHP4	TUBAL3	psi-mi:“MI:2364”(proximity)	0.270
B9D1	TXNDC9	psi-mi:“MI:2364”(proximity)	0.270
PINX1	INVS	psi-mi:“MI:0915”(physical association)	0.000
INVS	CHCHD6	psi-mi:“MI:0915”(physical association)	0.000
TRAF3IP2	INVS	psi-mi:“MI:0915”(physical association)	0.000
HIF1AN	INVS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): HIF1AN (Two-hybrid), INVS (Proximity Label-MS), INVS (Proximity Label-MS), INVS (Affinity Capture-MS), INVS (Affinity Capture-MS), CHCHD6 (Affinity Capture-MS), INVS (Affinity Capture-MS), INVS (Affinity Capture-RNA), INVS (Affinity Capture-MS), INVS (Affinity Capture-MS), NPHP1 (Affinity Capture-Western), INVS (Affinity Capture-Western), INVS (Affinity Capture-RNA), INVS (Affinity Capture-MS), INVS (Affinity Capture-MS)

ESM2 similar proteins: A0A0A6YYL3, A0A0R4I9Y1, A0JP26, A2A761, A6NI47, A6QR20, B2RU33, B7ZQJ9, F1M5M3, H3BUK9, O15050, O89019, P0C7A2, P29352, P51954, P98182, Q4UJ75, Q5CZ79, Q5DW34, Q5SQ80, Q5TKR9, Q5TYW2, Q5VUR7, Q6JAN1, Q6NSI1, Q6NYJ3, Q6S545, Q6S5H5, Q6S8J7, Q71S21, Q71S22, Q7TSC3, Q7ZT11, Q7ZXG4, Q80YD3, Q811D2, Q86YR6, Q8BZ21, Q8N157, Q8N2N9

Diamond homologs: A2ARS0, B2RXR6, C9JTQ0, L7XCU0, L7XDS4, O15084, O75762, O89019, P25799, Q00653, Q18297, Q2TB02, Q3EC11, Q3KP44, Q3SX00, Q4JHE0, Q4ULZ2, Q502K3, Q505D1, Q5F478, Q5R8C8, Q5U464, Q5ZLC8, Q61982, Q6JAN1, Q6RI86, Q810B6, Q86W74, Q8BLD6, Q8BTI7, Q8N8A2, Q8NB46, Q8UVC3, Q94B55, Q9R172, Q9UM47, Q9WTK5, Q9Y283, A0A096LNW5, A2RUV0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
INVS	down-regulates	DVL1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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
Organelle biogenesis and maintenance	6	24.8×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1156 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	83
Likely pathogenic	37
Uncertain significance	494
Likely benign	416
Benign	32

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073845	NC_000009.11:g.(?103008898)(103009069_?)del	Pathogenic
1074737	NM_014425.5(INVS):c.2729del (p.Lys910fs)	Pathogenic
1179160	GRCh37/hg19 9q31.1(chr9:103059178-103060312)	Pathogenic
11961	NM_014425.5(INVS):c.2719C>T (p.Arg907Ter)	Pathogenic
11963	NM_014425.5(INVS):c.1453del (p.Gln485fs)	Pathogenic
1252044	NM_014425.5(INVS):c.753T>G (p.Tyr251Ter)	Pathogenic
1350711	NM_014425.5(INVS):c.1811_1812del (p.Lys604fs)	Pathogenic
1399574	NM_014425.5(INVS):c.2801del (p.Lys934fs)	Pathogenic
1421657	NC_000009.11:g.(?103027084)(103035378_?)del	Pathogenic
1453877	NC_000009.11:g.(?103014545)(103015438_?)del	Pathogenic
1455250	NM_014425.5(INVS):c.83del (p.Gly28fs)	Pathogenic
1459019	NM_014425.5(INVS):c.1760del (p.Gln587fs)	Pathogenic
1459915	NM_014425.5(INVS):c.2372dup (p.Lys792fs)	Pathogenic
1908331	NM_014425.5(INVS):c.2659C>T (p.Gln887Ter)	Pathogenic
194404	NM_014425.5(INVS):c.2509C>T (p.Gln837Ter)	Pathogenic
2011057	NM_014425.5(INVS):c.2996C>G (p.Ser999Ter)	Pathogenic
2019816	NM_014425.5(INVS):c.983G>A (p.Trp328Ter)	Pathogenic
2020604	NM_014425.5(INVS):c.1566_1567AG[4] (p.Tyr525fs)	Pathogenic
2038526	NM_014425.5(INVS):c.321G>A (p.Trp107Ter)	Pathogenic
2109619	NM_014425.5(INVS):c.2116del (p.Arg706fs)	Pathogenic
2123868	NM_014425.5(INVS):c.1717A>T (p.Lys573Ter)	Pathogenic
2124136	NM_014425.5(INVS):c.1812del (p.Glu605fs)	Pathogenic
2137581	NM_014425.5(INVS):c.1663C>T (p.Gln555Ter)	Pathogenic
2421205	NM_014425.5(INVS):c.342_343del (p.Glu114fs)	Pathogenic
242358	NM_014425.5(INVS):c.1417del (p.Ala473fs)	Pathogenic
242360	NM_014425.5(INVS):c.2782C>T (p.Arg928Ter)	Pathogenic
2498124	NM_014425.5(INVS):c.805_806del (p.Gln269fs)	Pathogenic
2584431	NM_014425.5(INVS):c.325C>T (p.Gln109Ter)	Pathogenic
2697045	NM_014425.5(INVS):c.2230C>T (p.Gln744Ter)	Pathogenic
2712588	NM_014425.5(INVS):c.1211del (p.Asp404fs)	Pathogenic

SpliceAI

4535 predictions. Top by Δscore:

Variant	Effect	Δscore
9:100099415:GG:G	donor_gain	1.0000
9:100099416:GG:G	donor_gain	1.0000
9:100099417:G:GG	donor_gain	1.0000
9:100104492:TTTCA:T	acceptor_loss	1.0000
9:100104495:CA:C	acceptor_loss	1.0000
9:100104496:A:AG	acceptor_gain	1.0000
9:100104496:A:C	acceptor_loss	1.0000
9:100104496:AG:A	acceptor_gain	1.0000
9:100104496:AGGTT:A	acceptor_gain	1.0000
9:100104497:G:GC	acceptor_loss	1.0000
9:100104497:G:GG	acceptor_gain	1.0000
9:100104497:GG:G	acceptor_gain	1.0000
9:100104497:GGTT:G	acceptor_gain	1.0000
9:100104497:GGTTG:G	acceptor_gain	1.0000
9:100104623:CGTAG:C	donor_loss	1.0000
9:100104624:GTAG:G	donor_gain	1.0000
9:100104626:AGG:A	donor_loss	1.0000
9:100104627:GGTAA:G	donor_loss	1.0000
9:100104628:G:GG	donor_gain	1.0000
9:100104629:T:A	donor_loss	1.0000
9:100126373:A:AG	acceptor_gain	1.0000
9:100126374:T:G	acceptor_gain	1.0000
9:100126379:A:AG	acceptor_gain	1.0000
9:100126379:ATAG:A	acceptor_gain	1.0000
9:100126380:T:G	acceptor_gain	1.0000
9:100126380:TAGGA:T	acceptor_loss	1.0000
9:100126381:A:AG	acceptor_gain	1.0000
9:100126381:A:AT	acceptor_loss	1.0000
9:100126381:AG:A	acceptor_gain	1.0000
9:100126382:G:GC	acceptor_gain	1.0000

AlphaMissense

6981 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:100229670:T:C	L153P	1.000
9:100229678:A:C	S156R	1.000
9:100229680:T:A	S156R	1.000
9:100229680:T:G	S156R	1.000
9:100229715:T:C	L168P	1.000
9:100229756:G:C	G182R	1.000
9:100229757:G:T	G182V	1.000
9:100229766:C:A	P185Q	1.000
9:100229766:C:G	P185R	1.000
9:100229769:T:A	L186H	1.000
9:100240090:T:A	W216R	1.000
9:100240090:T:C	W216R	1.000
9:100240092:G:C	W216C	1.000
9:100240092:G:T	W216C	1.000
9:100240096:G:C	D218H	1.000
9:100240097:A:C	D218A	1.000
9:100240097:A:T	D218V	1.000
9:100240105:G:C	G221R	1.000
9:100240109:G:C	R222P	1.000
9:100240115:C:A	P224H	1.000
9:100240118:T:A	L225H	1.000
9:100240118:T:C	L225P	1.000
9:100240130:T:A	V229D	1.000
9:100240163:T:C	L240S	1.000
9:100240198:G:C	D252H	1.000
9:100240198:G:T	D252Y	1.000
9:100240199:A:C	D252A	1.000
9:100240199:A:T	D252V	1.000
9:100240211:G:C	R256P	1.000
9:100240225:T:A	W261R	1.000

dbSNP variants (sampled 300 via entrez): RS1000011949 (9:100175455 C>G), RS1000024434 (9:100186909 G>T), RS1000047899 (9:100228533 G>T), RS1000077367 (9:100190363 T>C), RS1000079632 (9:100181000 A>G,T), RS1000088148 (9:100293489 T>C), RS1000143737 (9:100174923 A>G), RS1000148124 (9:100235126 C>G), RS1000162238 (9:100228210 C>G,T), RS1000182521 (9:100273057 A>C), RS1000183986 (9:100180591 T>C), RS1000188256 (9:100138324 T>C,G), RS1000219135 (9:100197509 G>A), RS1000219227 (9:100138504 A>C,G), RS1000223263 (9:100276551 C>T)

Disease associations

OMIM: gene MIM:243305 | disease phenotypes: MIM:602088, MIM:256100

GenCC curated gene-disease

Disease	Classification	Inheritance
nephronophthisis 2	Definitive	Autosomal recessive
Senior-Loken syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nephronophthisis 2	Definitive	AR

Mondo (7): nephronophthisis 2 (MONDO:0011190), nephronophthisis (MONDO:0019005), kidney disorder (MONDO:0005240), kidney failure (MONDO:0001106), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), Senior-Loken syndrome (MONDO:0017842)

Orphanet (3): Nephronophthisis (Orphanet:655), Infantile nephronophthisis (Orphanet:93591), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000090	Nephronophthisis
HP:0000105	Enlarged kidney
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000556	Retinal dystrophy
HP:0000822	Hypertension
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001562	Oligohydramnios
HP:0001696	Situs inversus totalis
HP:0002089	Pulmonary hypoplasia
HP:0002093	Respiratory insufficiency
HP:0002153	Hyperkalemia
HP:0002612	Congenital hepatic fibrosis
HP:0002878	Respiratory failure
HP:0003259	Elevated circulating creatinine concentration
HP:0003774	Stage 5 chronic kidney disease
HP:0004322	Short stature
HP:0004348	Abnormality of bone mineral density
HP:0004719	Hyperechogenic kidneys
HP:0004734	Renal cortical microcysts
HP:0004743	Chronic tubulointerstitial nephritis
HP:0005564	Absence of renal corticomedullary differentiation
HP:0005976	Hyperkalemic metabolic acidosis
HP:0007703	Abnormal retinal pigmentation
HP:0008209	Premature ovarian insufficiency
HP:0010444	Pulmonic regurgitation
HP:0010579	Cone-shaped epiphysis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001949_11	Preeclampsia	2.000000e-06
GCST006976_30	Macular thickness	3.000000e-19

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D051437	Renal Insufficiency	C12.050.351.968.419.780; C12.200.777.419.780; C12.950.419.780
D058499	Retinal Dystrophies	C11.768.585.658
C566582	Nephronophthisis 2 (supp.)
C537580	Senior Loken Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10123866	Efficacy	3	duloxetine	Major Depressive Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10123866	INVS	3	0.00	1	duloxetine
rs7472	INVS, TEX10	3	0.00	1	duloxetine

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
bisphenol A	affects cotreatment, increases methylation, increases expression, decreases expression	3
Benzo(a)pyrene	decreases expression	3
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Valproic Acid	decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	decreases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
bisphenol S	decreases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Glyphosate	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methotrexate	increases expression	1
Zinc	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2ZC	Abcam HEK293T INVS KO	Transformed cell line	Female
CVCL_D9HA	Ubigene HEK293 INVS KO	Transformed cell line	Female
CVCL_E0F8	Ubigene HeLa INVS KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient
NCT02761577	PHASE4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia
NCT03029351	PHASE4	TERMINATED	GLP-1 Receptor Agonist Therapy and Albuminuria in Patients With Type 2 Diabetes