INPP5E

Chr 9AR

inositol polyphosphate-5-phosphatase E

NCBI Gene: 56623ENSG00000148384UniProt: Q9NRR6

Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (By similarity) (PubMed:10764818). Specific for lipid substrates, inactive towards water soluble inositol phosphates (PubMed:10764818). Plays an essential role in the primary cilium by controlling ciliary growth and phosphoinositide 3-kinase (PI3K) signaling and stability (By similarity)

Primary Disease Associations & Inheritance

Impaired intellectual development, truncal obesity, retinal dystrophy, and micropenis syndromeMIM #610156
AR
Joubert syndrome 1MIM #213300
AR
1043
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— INPP5E
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
1043 total variants — no pathogenic classifications of 1043 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.68LOEUF
pLI 0.003
Z-score 2.68
OE 0.37 (0.22–0.68)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.51Z-score
OE missense 0.93 (0.85–1.01)
355 obs / 382.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.22–0.68)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.85–1.01)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 8 / 21.4Missense obs/exp: 355 / 382.9Syn Z: -0.99

ClinVar Variant Classifications

1043 submitted variants in ClinVar

ClinVar

Classification Summary

Protein Context — Lollipop Plot

INPP5E · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

INPP5E-related intellectual development disorder, truncal obesity, retinal dystrophy, and micropenis

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. DisordersEye
G2P ↗
frameshift variantstop gained NMD escaping

INPP5E-related Joubert syndrome

definitive
ARLoss Of FunctionAltered Gene Product Structure, Uncertain
Dev. DisordersEye
G2P ↗
missense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Impaired intellectual development, truncal obesity, retinal dystrophy, and micropenis syndrome

MIM #610156

Molecular basis of disorder known

Autosomal recessive

Joubert syndrome 1

MIM #213300

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
Birtel J et al.·Sci Rep
2018Cohort
Potential Involvements of Cilia-Centrosomal Genes in Primary Congenital Glaucoma.
Pyatla G et al.·Int J Mol Sci
2024
Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders.
de Goede C et al.·Eur J Paediatr Neurol
2016Review
BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan.
Khan S et al.·Ann Hum Genet
2019
Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders.
Travaglini L et al.·Eur J Hum Genet
2013
Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders.
Radha Rama Devi A et al.·Pediatr Neurol
2020
MKS1 regulates ciliary INPP5E levels in Joubert syndrome.
Slaats GG et al.·J Med Genet
2016
A novel recurrent ARL3 variant c.209G > A p.(Gly70Glu) causes variable non-syndromic dominant retinal dystrophy with defective lipidated protein transport in human retinal stem cell models.
Corral-Serrano JC et al.·Hum Mol Genet
2025Functional
Biallelic pathogenic TULP3 variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations.
Li JQ et al.·J Med Genet
2025Case report
Pituitary stalk interruption syndrome is characterized by genetic heterogeneity.
Brauner R et al.·PLoS One
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools