INPPL1

Chr 11AR

inositol polyphosphate phosphatase like 1

Also known as: OPSMD, SHIP2

NCBI Gene: 3636 ENSG00000165458 UniProt: O15357 OMIM: 600829

The protein is a phosphatidylinositol phosphatase that hydrolyzes PtdIns(3,4,5)P3 to negatively regulate PI3K signaling pathways and plays essential roles in actin cytoskeleton remodeling, cell adhesion, mitotic spindle orientation, and endochondral ossification. Biallelic mutations cause opsismodysplasia, a severe skeletal dysplasia with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variation (LOEUF 0.423), indicating strong selective pressure for normal gene function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is an SH2-containing 5'-inositol phosphatase that is involved in the regulation of insulin function. The encoded protein also plays a role in the regulation of epidermal growth factor receptor turnover and actin remodelling. Additionally, this gene supports metastatic growth in breast cancer and is a valuable biomarker for breast cancer. [provided by RefSeq, Jan 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.421 OMIM phenotype

Clinical Summary— INPPL1

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Gene-Disease Validity (ClinGen)

opsismodysplasia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

48 unique Pathogenic / Likely Pathogenic· 317 VUS of 763 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — INPPL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.002

Z-score 5.17

OE 0.28 (0.19–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.60Z-score

OE missense 0.83 (0.78–0.89)

620 obs / 742.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.28 (0.19–0.42)

0≤0.351.4

Missense OE?0.83 (0.78–0.89)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 17 / 60.3Missense obs/exp: 620 / 742.9Syn Z: -0.65

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveINPPL1-related opsismodysplasiaOTHERAR

This gene — mechanism propensity

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

0.5674th %ile

GOF

0.6541th %ile

LOF

0.3841th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

763 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic19

VUS317

Likely Benign318

Benign37

Conflicting7

Pathogenic

Likely Pathogenic

317

VUS

318

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	22	4	3	0	29
Likely Pathogenic	17	2	0	0	19
VUS	2	298	12	5	317
Likely Benign	0	6	126	186	318
Benign	0	2	28	7	37
Conflicting	—				7
Total	41	312	169	198	727

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap INPPL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →