INVS

Chr 9AR

inversin

Also known as: INV, NPH2, NPHP2

NCBI Gene: 27130 ENSG00000119509 UniProt: Q9Y283 OMIM: 243305

The protein contains multiple ankyrin domains and functions as a molecular switch in Wnt signaling pathways, targeting disheveled for degradation and organizing apical junctions in kidney cells to support normal renal development and left-right axis determination. Mutations cause nephronophthisis type 2, an infantile-onset autosomal recessive ciliopathy affecting the kidneys. The gene is not highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Nephronophthisis 2, infantileMIM #602088

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · nephronophthisis 2 · AR · ClinGen 2021

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.92

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — INVS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 2.02

OE 0.69 (0.53–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.07Z-score

OE missense 0.87 (0.81–0.94)

502 obs / 574.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.69 (0.53–0.92)

0≤0.351.4

Missense OE?0.87 (0.81–0.94)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 35 / 50.5Missense obs/exp: 502 / 574.1Syn Z: 0.65

Background carrier burden — how many people carry a rare variant somewhere in INVS?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 61

1,255 rare PASS variants

Rare truncating (LoF)

1 in 620

218 rare PASS variants

Rare synonymous (reference)

1 in 92

483 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for INVS. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 660
South Asian	~43k	1 in 40	1 in 370
Remaining (unassigned)	~30k	1 in 43	1 in 370
European (Finnish)	~27k	1 in 190	≈ 1 in 5,300
Admixed American	~22k	1 in 47	1 in 460
African / African American	~21k	1 in 44	1 in 310
East Asian	~20k	1 in 66	1 in 520
Ashkenazi Jewish	~13k	1 in 220	1 in 1,900
Middle Eastern	~2,884	1 in 48	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.