# NM_001378452.1(ITPR1):c.195C>G (p.Arg65=)

https://sugi.bio/variant/itpr1-p-arg65

## Summary

**ITPR1 p.Arg65= (c.195C>G)** is classified **Benign** in ITPR1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Low-frequency (popmax 1.52%, sas); Associated with autosomal dominant cerebellar ataxia.

**At a glance:** Benign · review: Multiple submitters · rsID rs563347395 · 7 submitters · 1 linked condition · low-frequency (popmax 1.52%, sas)

## For patients & families {#patients}

This is a change in the ITPR1 gene that is classified as benign — not considered disease-causing, submitted by 7 submitters, and is linked to autosomal dominant cerebellar ataxia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 52 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004346/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ITPR1](https://sugi.bio/atlas/gene/ITPR1/) |
| Protein change (HGVS p.) | p.Arg65= |
| Coding change (HGVS c.) | c.195C>G |
| MANE Select transcript | [NM_001378452](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378452) |
| dbSNP | [rs563347395](https://www.ncbi.nlm.nih.gov/snp/rs563347395/) |
| Variant type | single nucleotide variant |
| Location | chr3:4627794-4627794 (GRCh38) |
| ClinVar | [VCV345544](https://www.ncbi.nlm.nih.gov/clinvar/variation/345544/) |

**All HGVS expressions:** `NC_000003.11:g.4669478C>G`, `NC_000003.12:g.4627794C>G`, `NG_016144.1:g.139447C>G`, `NM_001099952.4:c.195C>G`, `NM_001168272.2:c.195C>G`, `NM_001378452.1:c.195C>G`, `NM_002222.7:c.195C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.553, GERP 0.309, phastCons 0.994 — weakly conserved position
- CADD: **PHRED 9.305**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.52%** (sas) · FAF95 1.45% · FAF99 1.43% · 1,384/91,040 in the highest group · 1,473/1,613,640 alleles overall — low-frequency (popmax 1.52%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 1.52% | 66 |
| Remaining individuals (not grpmax-eligible) | 0.072% | 1,388 |
| Middle Eastern | 0.0495% | 2,020 |
| African / African-American | 0.00533% | 18,746 |
| European (non-Finnish) | 0.00314% | 31,884 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ITPR1** population constraint: LOEUF 0.325, pLI 1, missense-Z 6.2207; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **spinocerebellar ataxia type 29** — Definitive (AD)
- **aniridia-cerebellar ataxia-intellectual disability syndrome** — Definitive (AD)
- **aniridia-cerebellar ataxia-intellectual disability syndrome** — Definitive (AR)

## What this gene does {#gene-function}

*Describes the biological roles of ITPR1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ITPR1's established molecular role includes inositol 1,4,5-trisphosphate-gated calcium channel activity. In Reactome, ITPR1 is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**.

**Disease mechanism (Reactome):** ITPR1 loss or alteration is curated in [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323).

### Pathways affected {#pathways}

ITPR1 participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | electronic |
| [Effects of PIP2 hydrolysis](https://reactome.org/content/detail/R-HSA-114508) | curated |
| [Elevation of cytosolic Ca2+ levels](https://reactome.org/content/detail/R-HSA-139853) | curated |
| [Glucagon-like Peptide-1 (GLP1) regulates insulin secretion](https://reactome.org/content/detail/R-HSA-381676) | curated |
| [cGMP effects](https://reactome.org/content/detail/R-HSA-418457) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [CLEC7A (Dectin-1) induces NFAT activation](https://reactome.org/content/detail/R-HSA-5607763) | electronic |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | electronic |
| [DAG and IP3 signaling](https://reactome.org/content/detail/R-HSA-1489509) | electronic |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | electronic |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | electronic |
| [PLC beta mediated events](https://reactome.org/content/detail/R-HSA-112043) | electronic |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | electronic |
| [Role of phospholipids in phagocytosis](https://reactome.org/content/detail/R-HSA-2029485) | electronic |
| [VEGFR2 mediated cell proliferation](https://reactome.org/content/detail/R-HSA-5218921) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** inositol 1,4,5-trisphosphate-gated calcium channel activity, calcium channel inhibitor activity.

**Biological process:** response to hypoxia, regulation of calcium-mediated signaling, negative regulation of calcium-mediated signaling, release of sequestered calcium ion into cytosol, release of sequestered calcium ion into cytosol by endoplasmic reticulum.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** unanimous (7/7 Benign).

**Submission history:** 6 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2020-11-27 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-04-16 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2024-04-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2023-12-01 |

## Associated conditions {#conditions}

[autosomal dominant cerebellar ataxia](https://sugi.bio/atlas/disease/autosomal-dominant-cerebellar-ataxia/).

**Reported phenotype names (ClinVar):** Autosomal dominant cerebellar ataxia, not provided, not specified, ITPR1-related disorder, Spinocerebellar Ataxia, Dominant, AllHighlyPenetrant, ITPR1-related condition, none provided.

## Similar variants {#similar}

Related ITPR1 variant pages (same residue, condition, or type): [ITPR1 c.*1531G>A](/variant/itpr1-c-star-1531g-a), [ITPR1 p.Arg1761Gln](/variant/itpr1-p-arg1761gln), [ITPR1 p.Arg343Lys](/variant/itpr1-p-arg343lys), [ITPR1 p.Asp1959Asn](/variant/itpr1-p-asp1959asn), [ITPR1 p.Glu2128Val](/variant/itpr1-p-glu2128val), [ITPR1 p.Gly1782Arg](/variant/itpr1-p-gly1782arg), [ITPR1 p.Met2750Val](/variant/itpr1-p-met2750val), [ITPR1 p.Ser2180Asn](/variant/itpr1-p-ser2180asn).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 345544). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*