# NM_002224.4(ITPR3):c.1009G>C (p.Ala337Pro)

https://sugi.bio/variant/itpr3-p-ala337pro

## Summary

**ITPR3 p.Ala337Pro (c.1009G>C)** is classified **Uncertain significance** in ITPR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely benign (0.07); Very rare (popmax 0.000339%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the ITPR3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ITPR3](https://sugi.bio/atlas/gene/ITPR3/) |
| Protein change (HGVS p.) | p.Ala337Pro |
| Coding change (HGVS c.) | c.1009G>C |
| MANE Select transcript | [NM_002224](https://www.ncbi.nlm.nih.gov/nuccore/NM_002224) |
| Variant type | single nucleotide variant |
| Location | chr6:33663741-33663741 (GRCh38) |
| ClinVar | [VCV4040468](https://www.ncbi.nlm.nih.gov/clinvar/variation/4040468/) |

**All HGVS expressions:** `NC_000006.11:g.33631518G>C`, `NC_000006.12:g.33663741G>C`, `NG_027729.1:g.47363G>C`, `NG_027729.2:g.47421G>C`, `NM_002224.4:c.1009G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.07)
- REVEL 0.235 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.644 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.926, GERP -0.589 — weakly conserved position
- CADD: **PHRED 16.5**. 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.*
- Regional missense constraint: **o/e 0.81** across the covering region of the MANE Select transcript (33,662,574–33,676,848), spanning 14,274 bp. Chi-square p 5e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.23 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,978 in the highest group · 4/1,613,638 alleles overall — very rare (popmax 0.000339%, nfe).

*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}

**ITPR3** population constraint: LOEUF 0.67, pLI 1.3807e-29, missense-Z 5.2792. *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):

- **Charcot-Marie-Tooth disease, demyelinating, type 1J** — Definitive (AD)

## Protein context {#protein}

Residue **337** lies in the mir 4 domain; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 74.04, 3% of residues very-high.

**24 experimental structure(s)** (PDB): [6DQJ](https://www.rcsb.org/structure/6DQJ), [6DQN](https://www.rcsb.org/structure/6DQN), [6DQS](https://www.rcsb.org/structure/6DQS), [6DQV](https://www.rcsb.org/structure/6DQV), [6DQZ](https://www.rcsb.org/structure/6DQZ), [6DR0](https://www.rcsb.org/structure/6DR0).

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

*Describes the biological roles of ITPR3 (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:** ITPR3's established molecular role includes inositol 1,4,5-trisphosphate-gated calcium channel activity. p.Ala337Pro falls in the mir 4 domain. In Reactome, ITPR3 is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**.

**Disease mechanism (Reactome):** ITPR3 loss or alteration is curated in [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323).

### Pathways affected {#pathways}

ITPR3 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 |
| [Sensory perception of sweet, bitter, and umami (glutamate) taste](https://reactome.org/content/detail/R-HSA-9717207) | 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 ion binding, ATP binding, zinc ion binding, intracellularly gated calcium channel activity, inositol 1,4,5 trisphosphate binding.

**Biological process:** platelet activation, release of sequestered calcium ion into cytosol, protein homotetramerization, response to calcium ion, calcium ion homeostasis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-09.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-09 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ITPR3 variant pages (same residue, condition, or type): [ITPR3 p.Ala337Val](/variant/itpr3-p-ala337val), [ITPR3 p.Thr1424Met](/variant/itpr3-p-thr1424met), [ITPR3 p.Ala1352Thr](/variant/itpr3-p-ala1352thr), [ITPR3 p.Arg1085Leu](/variant/itpr3-p-arg1085leu), [ITPR3 p.Arg2659Cys](/variant/itpr3-p-arg2659cys), [ITPR3 p.Asp1968Val](/variant/itpr3-p-asp1968val), [ITPR3 p.Glu669Asp](/variant/itpr3-p-glu669asp), [ITPR3 p.Gly1008Trp](/variant/itpr3-p-gly1008trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4040468). 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.*