INPP4A

Chr 2AR

inositol polyphosphate-4-phosphatase type I A

Also known as: INPP4, NEDGQS, TVAS1

NCBI Gene: 3631 ENSG00000040933 UniProt: Q96PE3 OMIM: 600916

The protein is an inositol phosphatase that hydrolyzes phosphatidylinositol 3,4-bisphosphate and inositol phosphates, regulating PI3K-AKT signaling and protecting neurons from excitotoxic death. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.25), indicating intolerance to functional disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.251 OMIM phenotype

Clinical Summary— INPP4A

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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.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 89 VUS of 145 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.13 (0.07–0.25)

0≤0.351.4

Missense OE?0.61 (0.56–0.67)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 7 / 52.8Missense obs/exp: 357 / 584.7Syn Z: 0.69

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateINPP4A-related neurodevelopmental disorder with spasticity, epilepsy and cerebellar hypoplasiaLOFAR

This gene — mechanism propensity

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

0.4190th %ile

GOF

0.4579th %ile

LOF

0.70top 10%

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

145 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic2

VUS89

Likely Benign9

Benign7

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	1	2	0	8
Likely Pathogenic	1	0	0	1	2
VUS	0	89	0	0	89
Likely Benign	0	3	1	5	9
Benign	0	0	1	6	7
Total	6	93	4	12	115

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap INPP4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →