INPP5E

Chr 9AR

inositol polyphosphate-5-phosphatase E

Also known as: CORS1, CPD4, JBTS1, MORMS, PPI5PIV, pharbin

NCBI Gene: 56623 ENSG00000148384 UniProt: Q9NRR6 OMIM: 613037

The encoded phosphatidylinositol phosphatase hydrolyzes specific phosphoinositides and plays an essential role in primary cilium function by controlling ciliary growth and PI3K signaling. Mutations cause Joubert syndrome with characteristic midbrain-hindbrain malformation and associated ciliopathies including retinal dystrophy, nephronophthisis, liver fibrosis, and polydactyly, as well as a syndrome involving intellectual disability, truncal obesity, retinal dystrophy, and micropenis. Inheritance is autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. Studies of the mouse counterpart suggest that this protein may hydrolyze phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,5-bisphosphate on the cytoplasmic Golgi membrane and thereby regulate Golgi-vesicular trafficking. Mutations in this gene cause Joubert syndrome; a clinically and genetically heterogenous group of disorders characterized by midbrain-hindbrain malformation and various associated ciliopathies that include retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.682 OMIM phenotypes

Clinical Summary— INPP5E

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Gene-Disease Validity (ClinGen)

Joubert syndrome 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

81 unique Pathogenic / Likely Pathogenic· 404 VUS of 950 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — INPP5E

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?

0.68LOEUF

pLI 0.003

Z-score 2.68

OE 0.37 (0.22–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.51Z-score

OE missense 0.93 (0.85–1.01)

355 obs / 382.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.22–0.68)

0≤0.351.4

Missense OE?0.93 (0.85–1.01)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 8 / 21.4Missense obs/exp: 355 / 382.9Syn Z: -0.99

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveINPP5E-related intellectual development disorder, truncal obesity, retinal dystrophy, and micropenisLOFAR

definitiveINPP5E-related Joubert syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6356th %ile

GOF

0.6442th %ile

LOF

0.3941th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

950 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic48

VUS404

Likely Benign345

Benign50

Conflicting58

Pathogenic

Likely Pathogenic

404

VUS

345

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	25	7	1	0	33
Likely Pathogenic	23	25	0	0	48
VUS	9	348	43	4	404
Likely Benign	8	9	125	203	345
Benign	3	0	35	12	50
Conflicting	—				58
Total	68	389	204	219	938

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

77 pathogenic / likely-pathogenic (of 95) ClinVar copy-number / structural variants overlap INPP5E — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →