INVS

protein-coding

inversin, the group of Ankyrin repeat domain containing

Gene summary

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. [provided by RefSeq, May 2012]

Previous symbols:

NPHP2

MANE transcript

NM_014425.5

Inheritance

ClinVar variants

P:133U:484B:341

Top phenotype

Nephronophthisis 2

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr9:100,099,243-100,302,175

External References & Databases

Ensembl (ENSG00000119509)

Transcript & Mutation Effects

hg38 • Region Span ~202.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephronophthisis 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: PanelApp Australia

nephronophthisis 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: ClinGen

*INVS* was first reported in relation to autosomal recessive nephronophthisis-*INVS* in 2003 (Otto et al.; PMID: 12872123). At least 15 unique variants (missense, nonsense, frameshift) have been reported in 11 probands in 3 publications (PMIDs: 12872123, 19177160, 31706999). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene segregated with disease in one Bedouin family with 10 segregations (Haider et al. 1998; PMID: 9792867). The mechanism for disease is biallelic loss of function. This gene-disease association is supported by animal models and an expression study (PMIDs: 9744276, 26615802, 15852005). In summary, there is definitive evidence to support the relationship between *INVS* and autosomal recessive nephronophthisis-*INVS*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Expert Panel on the meeting date 2/24/21 (SOP Version 8). Data provided by the ClinGen Prenatal GCEP from June 11, 2025 secondary analysis Prenatal features have been seen as early as 14 weeks gestation. Most consistent and characteristic prenatal features include enlarged/echogenic kidneys with numerous small cysts. Other prenatal features observed are mega cisterna magna; vermis hypoplasia; cystic liver and pancreas; situs inversus totalis; ciliary dysgenesis; hydrops fetalis; oligohydramnios; and anhydramnios (PMIDs: 23713026, 24677454, 28749478, 31706999, 32335886, 37880672).

nephronophthisis 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: Labcorp Genetics (formerly Invitae)

nephronophthisis 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: Natera

nephronophthisis 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: Orphanet

Senior-Loken syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017842

Submitter: Orphanet

nephronophthisis 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Nephronophthisis 2AR

Manifestation: Gastrointestinal; Neurologic; Renal

Intervention: General

Rationale:

Refs: 2702088; 9792867; 12872123; 19177160; 20798123; 23559409

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to INVS variants in ClinVar

11 Conditions Cataloged

NephronophthisisTotal: 863

Infantile nephronophthisisTotal: 269

not providedTotal: 190

INVS-related disorderTotal: 163

Inborn genetic diseasesTotal: 151

not specifiedTotal: 103

INVS-related disordersTotal: 20

Retinal dystrophyTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014425.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	315 clinvar		323
missense		1 clinvar	462 clinvar	25 clinvar		488
nonsense	29 clinvar	18 clinvar	2 clinvar			49
start loss						0
frameshift	36 clinvar	27 clinvar	7 clinvar	1 clinvar		71
splice donor/acceptor (+/-2bp)	2 clinvar	20 clinvar	5 clinvar			27
Total	67	66	484	341	0	958

Highest pathogenic variant AF is 0.00009486701

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014425.5	RefSeq	NP_055240.2	16	MANE Select
ENST00000262457.7	Ensembl	ENSP00000262457.2	16	MANE Select
NM_001318381.2	RefSeq	NP_001305310.1	14	Standard
NM_001318382.2	RefSeq	NP_001305311.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
invs	Danio rerio	Structure: pronephric proximal convoluted tubule Quality: increased diameter abnormal

Gene / Model

Organism

Observed Phenotype

invs

Danio rerio

Structure: pronephric proximal convoluted tubule

Quality: increased diameter

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Wnt signaling pathway - Homo sapiens (human)
Wnt Signaling in Kidney Disease
Wnt Signaling Pathway

Biological Process

multicellular organism development
Wnt signaling pathway
negative regulation of canonical Wnt signaling pathway

Molecular Function

protein binding
calmodulin binding

Cellular Component

nucleus
cytoplasm
spindle
microtubule
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262457
Coding exons: 16
Length: 201745
Individuals with no LoFs: 125615
Homozygous LoFs: 0
Heterozygous LoFs: 133
Defined: 125748
p: 0.000529

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.07	502	574	0.874	0.0000309	6960
Missense (PolyPhen)		131	181.79	0.72062		2250
Synonymous	0.649	204	216	0.944	0.0000117	2112
Loss of Function	2.02	35	50.5	0.693	0.00000293	581

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00060	0.00060	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00062	0.00062	rare
South Asian	0.00052	0.00046	rare
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). {ECO:0000250, ECO:0000269|PubMed:15852005, ECO:0000269|PubMed:18371931}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:12872123}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.215

Intolerance Scores

LoFtool: 0.912
RVIS EVS: -0.57
RVIS percentile EVS: 19.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.831

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium