# NM_001378452.1(ITPR1):c.1867C>A (p.Arg623=)

https://sugi.bio/variant/itpr1-p-arg623

## Summary

**ITPR1 p.Arg623= (c.1867C>A)** is classified **Uncertain significance** in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). Very rare (popmax 0.00314%, nfe); Associated with aniridia-cerebellar ataxia-intellectual disability syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00314%, nfe)

## For patients & families {#patients}

This is a change in the ITPR1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to aniridia-cerebellar ataxia-intellectual disability syndrome.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000013/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.Arg623= |
| Coding change (HGVS c.) | c.1867C>A |
| MANE Select transcript | [NM_001378452](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378452) |
| Variant type | single nucleotide variant |
| Location | chr3:4667530-4667530 (GRCh38) |
| ClinVar | [VCV3773793](https://www.ncbi.nlm.nih.gov/clinvar/variation/3773793/) |

**All HGVS expressions:** `NC_000003.11:g.4709214C>A`, `NC_000003.12:g.4667530C>A`, `NG_016144.1:g.179183C>A`, `NG_016144.2:g.179184C>A`, `NM_001099952.4:c.1867C>A`, `NM_001168272.2:c.1822C>A`, `NM_001378452.1:c.1867C>A`, `NM_002222.7:c.1822C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.89) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.32, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.5**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.09**, acceptor gain **0.00**, donor gain **0.89**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.09**, acceptor gain **0.00**, donor gain **0.89**.
- Pangolin: Δ**0.65** (gain), gain 0.65 / loss 0.22. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00314%** (nfe) · FAF95 0.00232% · FAF99 0.00202% · 37/1,179,420 in the highest group · 38/1,612,870 alleles overall — very rare (popmax 0.00314%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00314% | 31,876 |
| African / African-American | 0.00134% | 74,860 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-08.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Genetics, Royal Melbourne Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-08 |

## Associated conditions {#conditions}

[aniridia-cerebellar ataxia-intellectual disability syndrome](https://sugi.bio/atlas/disease/aniridia-cerebellar-ataxia-intellectual-disability-syndrome/).

**Reported phenotype names (ClinVar):** Gillespie syndrome, Aniridia-cerebellar ataxia-intellectual disability syndrome, Aniridia, cerebellar ataxia, and mental deficiency.

## Same-residue context {#hotspot}

Residue **623** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ITPR1 p.Arg623Ter](/variant/itpr1-p-arg623ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ITPR1 variant pages (same residue, condition, or type): [ITPR1 p.Arg623Ter](/variant/itpr1-p-arg623ter), [ITPR1 p.Arg269Trp](/variant/itpr1-p-arg269trp), [ITPR1 p.Arg506Trp](/variant/itpr1-p-arg506trp), [ITPR1 p.Gly2554Arg](/variant/itpr1-p-gly2554arg), [ITPR1 p.Tyr567Cys](/variant/itpr1-p-tyr567cys), [ITPR1 p.Val1445Met](/variant/itpr1-p-val1445met), [ITPR1 p.Ala1222Thr](/variant/itpr1-p-ala1222thr), [ITPR1 p.Ala1480Thr](/variant/itpr1-p-ala1480thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3773793). 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.*