INPP4A

Chr 2AR

inositol polyphosphate-4-phosphatase type I A

Also known as: INPP4, NEDGQS, TVAS1

NCBI Gene: 3631ENSG00000040933UniProt: Q96PE3

This gene encodes an Mg++ independent enzyme that hydrolyzes the 4-position phosphate from the inositol ring of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate, and inositol 3,4-bisphosphate. Multiple transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Aug 2008]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speechMIM #621354
AR
161
ClinVar variants
25
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— INPP4A
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
25 Pathogenic / Likely Pathogenic· 91 VUS of 161 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.25LOEUF
pLI 1.000
Z-score 5.84
OE 0.13 (0.07–0.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
3.35Z-score
OE missense 0.61 (0.56–0.67)
357 obs / 584.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.13 (0.07–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.56–0.67)
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.0.94
0≤1.21.6
LoF obs/exp: 7 / 52.8Missense obs/exp: 357 / 584.7Syn Z: 0.69

ClinVar Variant Classifications

161 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic6
VUS91
Likely Benign8
Benign7
19
Pathogenic
6
Likely Pathogenic
91
VUS
8
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
15
0
19
Likely Pathogenic
1
0
4
1
6
VUS
0
87
4
0
91
Likely Benign
0
2
2
4
8
Benign
0
0
1
6
7
Total4902611131

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

View in ClinVar →

Protein Context — Lollipop Plot

INPP4A · protein map & ClinVar variants

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

Gene2Phenotype Curations

INPP4A-related neurodevelopmental disorder with spasticity, epilepsy and cerebellar hypoplasia

moderate
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. Disorders
G2P ↗
stop gainedmissense variantstop gained NMD escapingframeshift variant NMD escapingwhole partial gene deletion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech

MIM #621354

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families.
Al-Kasbi G et al.·Sci Rep
2022
Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.
Rawlins LE et al.·Genet Med
2025
INPP4A-related genetic and phenotypic spectrum and functional relevance of subcellular targeting of INPP4A isoforms.
Hecher L et al.·Neurogenetics
2023Case report
Deficiency of INPP4A promotes M2 macrophage polarization in eosinophilic chronic rhinosinusitis with nasal polyps.
Xu Y et al.·Inflamm Res
2024
A novel INPP4A mutation with pontocerebellar hypoplasia, myoclonic epilepsy, microcephaly, and severe developmental delay.
Özkan Kart P et al.·Brain Dev
2023Case report
Whole exome sequencing identified a novel nonsense INPP4A mutation in a family with intellectual disability.
Banihashemi S et al.·Eur J Med Genet
2020
A genetic variation in inositol polyphosphate 4 phosphatase a enhances susceptibility to asthma.
Sharma M et al.·Am J Respir Crit Care Med
2008
Hindbrain malformation and myoclonic seizures associated with a deleterious mutation in the INPP4A gene.
Sheffer R et al.·Neurogenetics
2015Case report
Exome sequencing in 51 early onset non-familial CRC cases.
Thutkawkorapin J et al.·Mol Genet Genomic Med
2019Cohort
miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma.
Lin C et al.·Nat Commun
2014
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools