INPP1

Chr 2

inositol polyphosphate-1-phosphatase

NCBI Gene: 3628 ENSG00000151689 UniProt: P49441 OMIM: 147263

The protein is a magnesium-dependent phosphatase that hydrolyzes the 1-position phosphate from inositol 1,4-bisphosphate and inositol 1,3,4-trisphosphate, participating in inositol phosphate metabolism. Mutations cause pontocerebellar hypoplasia type 10, characterized by progressive microcephaly, severe developmental delay, seizures, and brain atrophy affecting the brainstem and cerebellum, with autosomal recessive inheritance. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes the enzyme inositol polyphosphate-1-phosphatase, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 1 of the inositol ring from the polyphosphates inositol 1,4-bisphosphate and inositol 1,3,4-trisphophosphate. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.27

Clinical Summary— INPP1

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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

51 VUS of 71 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.27LOEUF

pLI 0.000

Z-score 0.81

OE 0.77 (0.48–1.27)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.18Z-score

OE missense 0.77 (0.68–0.88)

168 obs / 217.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.48–1.27)

0≤0.351.4

Missense OE?0.77 (0.68–0.88)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 11 / 14.3Missense obs/exp: 168 / 217.1Syn Z: 0.73

This gene — mechanism propensity

0.6840th %ile

GOF

0.4973th %ile

LOF

0.2483th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

71 submitted variants in ClinVar

ClinVar

Classification Summary

VUS51

Likely Benign5

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	50	0	51
Likely Benign	0	5	0	5
Benign	0	0	1	1
Total	1	55	1	57

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap INPP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →