ITPR1

Chr 3ADAR

inositol 1,4,5-trisphosphate receptor type 1

Also known as: ACV, CLA4, INSP3R1, IP3R, IP3R1, PPP1R94, SCA15, SCA16

NCBI Gene: 3708ENSG00000150995UniProt: Q14643

This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

Primary Disease Associations & Inheritance

Gillespie syndromeMIM #206700
ADAR
Spinocerebellar ataxia 15MIM #606658
AD
Spinocerebellar ataxia 29, congenital nonprogressiveMIM #117360
AD
550
ClinVar variants
23
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— ITPR1
🧬
Gene-Disease Validity (ClinGen)
spinocerebellar ataxia type 29 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡
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
23 Pathogenic / Likely Pathogenic· 327 VUS of 550 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.13LOEUF
pLI 1.000
Z-score 9.93
OE 0.08 (0.05–0.13)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
5.60Z-score
OE missense 0.59 (0.56–0.63)
895 obs / 1506.0 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.08 (0.05–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.56–0.63)
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.1.09
0≤1.21.6
LoF obs/exp: 11 / 136.0Missense obs/exp: 895 / 1506.0Syn Z: -1.71

ClinVar Variant Classifications

550 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic8
VUS327
Likely Benign194
Benign1
Conflicting5
15
Pathogenic
8
Likely Pathogenic
327
VUS
194
Likely Benign
1
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
13
0
15
Likely Pathogenic
2
4
2
0
8
VUS
4
289
31
3
327
Likely Benign
0
1
89
104
194
Benign
0
0
1
0
1
Conflicting
—5
Total7295136107550

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

View in ClinVar →

Protein Context — Lollipop Plot

ITPR1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ITPR1-related Gillespie Syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

ITPR1-related Gillespie Syndrome

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. DisordersEye
G2P ↗

ITPR1-related spinocerebellar ataxia, congenital nonprogressive

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Gillespie syndrome

MIM #206700

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Spinocerebellar ataxia 15

MIM #606658

Molecular basis of disorder known

Autosomal dominant

Spinocerebellar ataxia 29, congenital nonprogressive

MIM #117360

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ITPR1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.
Tolonen JP et al.·Mov Disord
2024
The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.
Monies D et al.·Hum Genet
2017
Autoimmune brainstem encephalitis: Clinical associations, outcomes, and proposed diagnostic criteria.
Gilligan M et al.·Ann Clin Transl Neurol
2025
A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.
Molitor A et al.·Sci Adv
2024
Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
Cunha P et al.·Am J Hum Genet
2023
Inositol 1,4,5-trisphosphate receptor type 1 autoantibody (ITPR1-IgG/anti-Sj)-associated autoimmune cerebellar ataxia, encephalitis and peripheral neuropathy: review of the literature.
Jarius S et al.·J Neuroinflammation
2022Review
The natural history of progressive myoclonus ataxia.
van der Veen S et al.·Neurobiol Dis
2024Natural history
A Review of Spinocerebellar Ataxias in Taiwan.
Lee CJ et al.·Acta Neurol Taiwan
2025Review
Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.
Zambonin JL et al.·Orphanet J Rare Dis
2017Review
Systematic analysis of the expression and prognostic value of ITPR1 and correlation with tumor infiltrating immune cells in breast cancer.
Han B et al.·BMC Cancer
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A Novel Gain-of-Function ITPR1 Variant Associated With a Movement Disorder Characterized by Tremor and Dystonia.
Théberge ET et al.·Am J Med Genet A
2026
Long non-coding RNA THAP7-AS1 interacts with EIF3A and enhances ITPR1 to enhance endoplasmic reticulum stress and endothelial cell pyroptosis in ischemic stroke.
Pan Y et al.·Brain Res Bull
2026
Expanding the Early Childhood Manifestations of ITPR1 Heterozygous Variants Beyond Congenital Ataxia and Gillespie Syndrome.
Terry LE et al.·Neurol Genet
2026🔓 Open Access
ITPR1 Deletion in a Patient With Sensory Ataxic Neuropathy and Sjögren Syndrome.
Haddad S et al.·J Peripher Nerv Syst
2025🔓 Open Access
Generation of an ITPR1+/- and isogenic control induced pluripotent stem cell line for SCA15/16 model development.
Masser-Mitchell BE et al.·Stem Cell Res
2025Functional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools