ITPR1

Chr 3ADAR

inositol 1,4,5-trisphosphate receptor type 1

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

NCBI Gene: 3708 ENSG00000150995 UniProt: Q14643 OMIM: 147265

This gene encodes an intracellular receptor that mediates calcium release from the endoplasmic reticulum upon inositol 1,4,5-trisphosphate binding. Mutations cause spinocerebellar ataxia types 15 and 29 (congenital nonprogressive) and Gillespie syndrome, with inheritance patterns that can be either autosomal dominant or autosomal recessive. The gene is highly constrained against loss-of-function variants, indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.133 OMIM phenotypes

Clinical Summary— ITPR1

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Gene-Disease Validity (ClinGen)

aniridia-cerebellar ataxia-intellectual disability syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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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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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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

0.13LOEUF

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

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

LoF OE0.08 (0.05–0.13)

0≤0.351.4

Missense OE0.59 (0.56–0.63)

0≤0.61.4

Synonymous OE1.09

0≤1.21.6

LoF obs/exp: 11 / 136.0Missense obs/exp: 895 / 1506.0Syn Z: -1.71

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveITPR1-related Gillespie SyndromeLOFAR

definitiveITPR1-related Gillespie SyndromeDNAD

strongITPR1-related spinocerebellar ataxia, congenital nonprogressiveOTHERAD

0.4189th %ile

GOF

0.6248th %ile

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.13

GOF1 literature citation

DN1 literature citation

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.

Literature Evidence

DNUsing estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negativPMID:27108798

GOFA novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca(2+) signal patterns.PMID:28620721

LOFOur data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15.PMID:17932120

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.