# NM_001382567.1(STIM1):c.859C>T (p.Arg287Cys)

https://sugi.bio/variant/stim1-p-arg287cys

## Summary

**STIM1 p.Arg287Cys (c.859C>T)** is classified **Uncertain significance** in STIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-15). AlphaMissense: likely benign (0.3047); Very rare (popmax 0.00801%, afr); Associated with tubular aggregate myopathy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1034949340 · 1 submitter · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00801%, afr)

## For patients & families {#patients}

This is a change in the STIM1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to tubular aggregate myopathy.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Diagnostic panels | STIM1 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Tubular aggregate myopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myalgia — Very frequent (99-80%)
- Muscle spasm — Very frequent (99-80%)
- EMG: myopathic abnormalities — Very frequent (99-80%)
- Fatigable weakness — Very frequent (99-80%)
- Fatiguable weakness of proximal limb muscles — Very frequent (99-80%)
- Muscle fiber tubular inclusions — Very frequent (99-80%)
- Increased variability in muscle fiber diameter — Frequent (79-30%)
- Centrally nucleated skeletal muscle fibers — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003884/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STIM1](https://sugi.bio/atlas/gene/STIM1/) |
| Protein change (HGVS p.) | p.Arg287Cys |
| Coding change (HGVS c.) | c.859C>T |
| MANE Select transcript | [NM_001382567](https://www.ncbi.nlm.nih.gov/nuccore/NM_001382567) |
| dbSNP | [rs1034949340](https://www.ncbi.nlm.nih.gov/snp/rs1034949340/) |
| Variant type | single nucleotide variant |
| Location | chr11:4074569-4074569 (GRCh38) |
| ClinVar | [VCV951660](https://www.ncbi.nlm.nih.gov/clinvar/variation/951660/) |

**All HGVS expressions:** `LRG_164:g.223867C>T`, `LRG_164t1:c.859C>T`, `NC_000011.10:g.4074569C>T`, `NC_000011.9:g.4095799C>T`, `NG_016277.1:g.223867C>T`, `NM_001277961.3:c.859C>T`, `NM_001277962.2:c.859C>T`, `NM_001382566.1:c.637C>T`, `NM_001382567.1:c.859C>T`, `NM_001382568.1:c.859C>T`, `NM_001382569.1:c.724C>T`, `NM_001382570.1:c.631C>T`, `NM_001382571.1:c.379C>T`, `NM_001382572.1:c.859C>T`, `NM_001382573.1:c.637C>T`, `NM_001382574.1:c.637C>T`, `NM_001382575.1:c.637C>T`, `NM_001382576.1:c.637C>T`, `NM_001382577.1:c.637C>T`, `NM_001382578.1:c.637C>T`, `NM_001382579.1:c.637C>T`, `NM_001382580.1:c.370C>T`, `NM_001382581.1:c.370C>T`, `NM_003156.4:c.859C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3047)
- REVEL 0.326 (indeterminate)
- SaProt LLR -9.115 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 5.953, GERP -0.225, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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 0.56** across the covering region of the MANE Select transcript (4,070,160–4,083,343), spanning 13,183 bp. Chi-square p 8.6e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00801%** (afr) · FAF95 0.00347% · FAF99 0.00229% · 6/74,896 in the highest group · 14/1,613,890 alleles overall — very rare (popmax 0.00801%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00801% | 12,483 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| European (non-Finnish) | 0.000593% | 168,571 |

*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}

**STIM1** population constraint: LOEUF 0.475, pLI 0.99496, missense-Z 2.5772. *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):

- **tubular aggregate myopathy** — Definitive (AD)
- **combined immunodeficiency due to STIM1 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **287** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 68.81, 22% of residues very-high.

**6 experimental structure(s)** (PDB): [2K60](https://www.rcsb.org/structure/2K60), [2MAJ](https://www.rcsb.org/structure/2MAJ), [2MAK](https://www.rcsb.org/structure/2MAK), [3TEQ](https://www.rcsb.org/structure/3TEQ), [4O9B](https://www.rcsb.org/structure/4O9B), [6YEL](https://www.rcsb.org/structure/6YEL).

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

*Describes the biological roles of STIM1 (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:** STIM1's established molecular role includes protease binding.


### Pathways affected {#pathways}

STIM1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [Elevation of cytosolic Ca2+ levels](https://reactome.org/content/detail/R-HSA-139853) | electronic |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | electronic |

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

**Molecular function:** protease binding, calcium channel regulator activity, calcium ion binding, identical protein binding, microtubule plus-end binding.

**Biological process:** store-operated calcium entry, detection of calcium ion, activation of store-operated calcium channel activity, positive regulation of adenylate cyclase activity, positive regulation of angiogenesis, regulation of calcium ion transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-15 |

## Associated conditions {#conditions}

[tubular aggregate myopathy](https://sugi.bio/atlas/disease/tubular-aggregate-myopathy/), [Stormorken syndrome](https://sugi.bio/atlas/disease/stormorken-syndrome/), [combined immunodeficiency due to STIM1 deficiency](https://sugi.bio/atlas/disease/combined-immunodeficiency-due-to-stim1-deficiency/).

**Reported phenotype names (ClinVar):** Myopathy with tubular aggregates, Combined immunodeficiency due to STIM1 deficiency, Stormorken syndrome, Tubular Aggregate Myopathy, THROMBOCYTOPATHY, ASPLENIA, AND MIOSIS, IMMUNODEFICIENCY 10, STIM1 DEFICIENCY.

## Similar variants {#similar}

Related STIM1 variant pages (same residue, condition, or type): [STIM1 p.Arg287=](/variant/stim1-p-arg287), [STIM1 p.Arg287His](/variant/stim1-p-arg287his), [STIM1 p.Arg287Ser](/variant/stim1-p-arg287ser), [STIM1 p.Arg304Trp](/variant/stim1-p-arg304trp), [STIM1 p.Arg50Ter](/variant/stim1-p-arg50ter), [STIM1 p.His109Arg](/variant/stim1-p-his109arg), [STIM1 p.Ser88Gly](/variant/stim1-p-ser88gly), [STIM1 c.792-3C>A](/variant/stim1-c-792-minus-3c-a).

### 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 951660). 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.*