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…

Primary Disease Associations & Inheritance

OpsismodysplasiaMIM #258480

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · opsismodysplasia · AR · ClinGen 2026

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.42

LOEUF

GOF

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in INPPL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 41

1,558 rare PASS variants

Rare truncating (LoF)

1 in 790

265 rare PASS variants

Rare synonymous (reference)

1 in 81

777 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for INPPL1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 52	1 in 820
South Asian	~43k	1 in 37	1 in 440
Remaining (unassigned)	~30k	1 in 42	1 in 920
European (Finnish)	~27k	1 in 110	1 in 810
Admixed American	~22k	1 in 37	1 in 1,700
African / African American	~21k	1 in 39	1 in 1,200
East Asian	~20k	1 in 49	1 in 1,300
Ashkenazi Jewish	~13k	1 in 210	1 in 1,100
Middle Eastern	~2,884	1 in 58	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 27 of 28 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 28.? see exons ↓