# NM_002223.4(ITPR2):c.6309T>C (p.Asp2103=)

https://sugi.bio/variant/itpr2-p-asp2103

## Summary

**ITPR2 p.Asp2103= (c.6309T>C)** is classified **Likely benign** in ITPR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-22). Ultra-rare (popmax 0.0201%, eas); Associated with ITPR2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs376442300 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0201%, eas)

## For patients & families {#patients}

This is a change in the ITPR2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ITPR2-related disorder.

*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 | [ITPR2](https://sugi.bio/atlas/gene/ITPR2/) |
| Protein change (HGVS p.) | p.Asp2103= |
| Coding change (HGVS c.) | c.6309T>C |
| MANE Select transcript | [NM_002223](https://www.ncbi.nlm.nih.gov/nuccore/NM_002223) |
| dbSNP | [rs376442300](https://www.ncbi.nlm.nih.gov/snp/rs376442300/) |
| Variant type | single nucleotide variant |
| Location | chr12:26475329-26475329 (GRCh38) |
| ClinVar | [VCV3038559](https://www.ncbi.nlm.nih.gov/clinvar/variation/3038559/) |

**All HGVS expressions:** `NC_000012.11:g.26628262A>G`, `NC_000012.12:g.26475329A>G`, `NG_042142.1:g.362870T>C`, `NM_001414174.1:c.6306T>C`, `NM_001414175.1:c.6123+5802T>C`, `NM_002223.4:c.6309T>C`

## 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 -0.186, GERP -4.96, phastCons 0.003 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.744**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.92 donor 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 **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.00779% · 9/44,860 in the highest group · 40/1,614,068 alleles overall — ultra-rare (popmax 0.0201%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.048% | 2,084 |
| East Asian (grpmax) | 0.0201% | 4,984 |
| South Asian | 0.0011% | 91,072 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ITPR2** population constraint: LOEUF 0.724, pLI 9.3592e-27, missense-Z 4.4861. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


**6 experimental structure(s)** (PDB): [9YKK](https://www.rcsb.org/structure/9YKK), [9YKY](https://www.rcsb.org/structure/9YKY), [9YLI](https://www.rcsb.org/structure/9YLI), [9YMZ](https://www.rcsb.org/structure/9YMZ), [9YNK](https://www.rcsb.org/structure/9YNK), [9YNO](https://www.rcsb.org/structure/9YNO).

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

*Describes the biological roles of ITPR2 (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:** ITPR2's established molecular role includes transmembrane transporter binding. In Reactome, ITPR2 is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**.

**Disease mechanism (Reactome):** ITPR2 loss or alteration is curated in [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323).

### Pathways affected {#pathways}

ITPR2 participates in **14 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 |
| [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:** transmembrane transporter binding, scaffold protein binding.

**Biological process:** response to hypoxia.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-05-22.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-05-22 |

## Associated conditions {#conditions}

[ITPR2-related disorder](https://sugi.bio/atlas/disease/itpr2-related-disorder/).

**Reported phenotype names (ClinVar):** ITPR2-related disorder, ITPR2-related condition.

## Similar variants {#similar}

Related ITPR2 variant pages (same residue, condition, or type): [ITPR2 c.279+6G>C](/variant/itpr2-c-279-plus-6g-c), [ITPR2 c.3122+4T>C](/variant/itpr2-c-3122-plus-4t-c), [ITPR2 c.3552+3C>T](/variant/itpr2-c-3552-plus-3c-t), [ITPR2 c.4381-8C>T](/variant/itpr2-c-4381-minus-8c-t), [ITPR2 p.Ala2112=](/variant/itpr2-p-ala2112), [ITPR2 p.Ala898=](/variant/itpr2-p-ala898), [ITPR2 p.Glu815=](/variant/itpr2-p-glu815), [ITPR2 p.Phe1958=](/variant/itpr2-p-phe1958).

### 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 3038559). 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.*