# NM_002223.4(ITPR2):c.2055A>G (p.Ser685=)

https://sugi.bio/variant/itpr2-p-ser685

## Summary

**ITPR2 p.Ser685= (c.2055A>G)** is classified **Benign** in ITPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-19). Common (popmax 61.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with isolated anhidrosis with normal sweat glands.

**At a glance:** Benign · review: Multiple submitters · rsID rs2291264 · 2 submitters · 1 linked condition · common (popmax 61.5%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ITPR2 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters, and is linked to isolated anhidrosis with normal sweat glands.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017843/index) · [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.Ser685= |
| Coding change (HGVS c.) | c.2055A>G |
| MANE Select transcript | [NM_002223](https://www.ncbi.nlm.nih.gov/nuccore/NM_002223) |
| dbSNP | [rs2291264](https://www.ncbi.nlm.nih.gov/snp/rs2291264/) |
| Variant type | single nucleotide variant |
| Location | chr12:26657844-26657844 (GRCh38) |
| ClinVar | [VCV1300050](https://www.ncbi.nlm.nih.gov/clinvar/variation/1300050/) |

**All HGVS expressions:** `NC_000012.11:g.26810777T>C`, `NC_000012.12:g.26657844T>C`, `NG_042142.1:g.180355A>G`, `NM_002223.4:c.2055A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 61.5%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 **acceptor loss** (Δ 0.46) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -5.955, GERP -3.17 — fast-evolving / accelerated position
- CADD: **PHRED 0.298**. 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 **0.46**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **61.5%** (eas) · FAF95 60.9% · FAF99 60.7% · 27,596/44,858 in the highest group · 589,195/1,613,192 alleles overall — common (popmax 61.5%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 61.5% | 2 |
| Admixed American | 52.5% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 46.9% | 2 |
| Amish (not grpmax-eligible) | 44.5% | 2 |
| South Asian | 38.9% | 3 |
| Finnish (not grpmax-eligible) | 37.8% | 3 |
| Remaining individuals (not grpmax-eligible) | 37.1% | 3 |
| European (non-Finnish) | 35.2% | 3 |
| Middle Eastern | 29.5% | 3 |
| African / African-American | 22% | 5 |

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-08-19.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-08-19 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[isolated anhidrosis with normal sweat glands](https://sugi.bio/atlas/disease/isolated-anhidrosis-with-normal-sweat-glands/).

**Reported phenotype names (ClinVar):** Isolated anhidrosis with normal sweat glands, not provided, DANN-EPSTEIN-SOHAR SYNDROME, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related ITPR2 variant pages (same residue, condition, or type): [ITPR2 c.3801+23G>A](/variant/itpr2-c-3801-plus-23g-a), [ITPR2 c.93-10T>A](/variant/itpr2-c-93-minus-10t-a), [ITPR2 p.Asp1413=](/variant/itpr2-p-asp1413), [ITPR2 p.Glu255=](/variant/itpr2-p-glu255), [ITPR2 p.His961=](/variant/itpr2-p-his961), [ITPR2 p.Lys1469=](/variant/itpr2-p-lys1469), [ITPR2 p.Thr2184Ser](/variant/itpr2-p-thr2184ser), [ITPR2 p.Asp632Tyr](/variant/itpr2-p-asp632tyr).

### 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 1300050). 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.*