Myopathy, tubular aggregate, 1

Summary

Myopathy, tubular aggregate, 1 (MONDO:0024531) is a disease caused by STIM1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: STIM1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 42

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, tubular aggregate, 1
Mondo ID	MONDO:0024531
OMIM	160565
UMLS	C4011726
MedGen	860163
GARD	0025414
Is cancer (heuristic)	no

Also known as: myopathy, tubular aggregate, 1 · STIM1 tubular aggregate myopathy · TAM1 · tubular aggregate myopathy caused by mutation in STIM1

Data availability: 42 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › tubular aggregate myopathy › myopathy, tubular aggregate, 1

Related subtypes (1): myopathy, tubular aggregate, 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

42 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 7 pathogenic, 6 conflicting classifications of pathogenicity, 4 likely pathogenic, 3 benign, 1 likely benign, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
665042	NC_000011.10:g.(?3856251)(4091818_?)del	LOC112081391	Pathogenic	criteria provided, single submitter
143191	NM_001382567.1(STIM1):c.343A>T (p.Ile115Phe)	STIM1	Pathogenic	criteria provided, single submitter
2683800	NM_001382567.1(STIM1):c.216C>G (p.His72Gln)	STIM1	Pathogenic	no assertion criteria provided
3061748	NM_001382567.1(STIM1):c.1453del (p.Val485fs)	STIM1	Pathogenic	criteria provided, single submitter
41481	NM_001382567.1(STIM1):c.251A>G (p.Asp84Gly)	STIM1	Pathogenic	criteria provided, single submitter
41482	NM_001382567.1(STIM1):c.325C>A (p.His109Asn)	STIM1	Pathogenic	no assertion criteria provided
41483	NM_001382567.1(STIM1):c.326A>G (p.His109Arg)	STIM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
643831	NM_001382567.1(STIM1):c.700_707del (p.Asn234fs)	STIM1	Pathogenic	criteria provided, single submitter
1679390	NM_001382567.1(STIM1):c.1403del (p.Pro468fs)	STIM1	Likely pathogenic	criteria provided, single submitter
189363	NM_001382567.1(STIM1):c.239A>C (p.Asn80Thr)	STIM1	Likely pathogenic	criteria provided, single submitter
3236678	NM_001382567.1(STIM1):c.252T>A (p.Asp84Glu)	STIM1	Likely pathogenic	criteria provided, single submitter
3256588	NM_001382567.1(STIM1):c.344T>C (p.Ile115Thr)	STIM1	Likely pathogenic	criteria provided, single submitter
568147	NM_001382567.1(STIM1):c.1847C>T (p.Ala616Val)	LOC124418421	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235347	NM_001382567.1(STIM1):c.1664C>T (p.Ser555Phe)	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
461722	NM_001382567.1(STIM1):c.1634+287G>A	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
506350	NM_001382567.1(STIM1):c.1634+269C>G	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
569843	NM_001382567.1(STIM1):c.454G>A (p.Glu152Lys)	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626025	NM_001382567.1(STIM1):c.1634+319G>A	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
649175	NM_001382567.1(STIM1):c.1838C>T (p.Ala613Val)	LOC124418421	Uncertain significance	criteria provided, single submitter
992542	NM_001382567.1(STIM1):c.2026C>G (p.Pro676Ala)	LOC124418421	Uncertain significance	criteria provided, multiple submitters, no conflicts
652118	NM_032790.4(ORAI1):c.37A>T (p.Ser13Cys)	ORAI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031286	NM_001382567.1(STIM1):c.1634+60G>A	STIM1	Uncertain significance	criteria provided, single submitter
1038769	NM_001382567.1(STIM1):c.464G>A (p.Arg155Gln)	STIM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333842	NM_001382567.1(STIM1):c.2124A>T (p.Lys708Asn)	STIM1	Uncertain significance	criteria provided, single submitter
2113642	NM_001382567.1(STIM1):c.718C>T (p.His240Tyr)	STIM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2143190	NM_001382567.1(STIM1):c.661G>A (p.Val221Ile)	STIM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2633685	NM_001382567.1(STIM1):c.1662_1673delinsACTCCCTCG (p.Ser555_Met558delinsLeuProArg)	STIM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2923740	NM_001382567.1(STIM1):c.1123G>C (p.Val375Leu)	STIM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236679	NM_001382567.1(STIM1):c.250G>A (p.Asp84Asn)	STIM1	Uncertain significance	criteria provided, single submitter
3780668	NM_001382567.1(STIM1):c.1634+245C>T	STIM1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
STIM1	Definitive	Autosomal dominant	myopathy, tubular aggregate, 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STIM1	Orphanet:2593	Tubular aggregate myopathy
STIM1	Orphanet:317430	Combined immunodeficiency due to STIM1 deficiency
STIM1	Orphanet:3204	Stormorken-Sjaastad-Langslet syndrome
ORAI1	Orphanet:2593	Tubular aggregate myopathy
ORAI1	Orphanet:317428	Combined immunodeficiency due to ORAI1 deficiency
ORAI1	Orphanet:3204	Stormorken-Sjaastad-Langslet syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STIM1	HGNC:11386	ENSG00000167323	Q13586	Stromal interaction molecule 1	gencc,clinvar
ORAI1	HGNC:25896	ENSG00000276045	Q96D31	Calcium release-activated calcium channel protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STIM1	Stromal interaction molecule 1	Acts as a Ca(2+) sensor that gates two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels.
ORAI1	Calcium release-activated calcium channel protein 1	Pore-forming subunit of two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STIM1	Other/Unknown	no		SAM, SAM/pointed_sf, SOAR_STIM1/2
ORAI1	Other/Unknown	no		CRAC_channel, Orai_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
gastrocnemius	1
muscle of leg	1
granulocyte	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STIM1	237	ubiquitous	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
ORAI1	177	ubiquitous	yes	granulocyte, hindlimb stylopod muscle, skin of leg

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STIM1	3,074
ORAI1	1,239

Intra-cohort edges

A	B	Sources
ORAI1	STIM1	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STIM1	Q13586	6
ORAI1	Q96D31	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Elevation of cytosolic Ca2+ levels	2	713.8×	2e-05	STIM1, ORAI1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	2	356.9×	4e-05	STIM1, ORAI1
Ion homeostasis	2	203.9×	9e-05	STIM1, ORAI1
Platelet calcium homeostasis	1	356.9×	0.008	STIM1
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.013	STIM1
Platelet homeostasis	1	139.3×	0.013	STIM1
Cardiac conduction	1	54.4×	0.029	STIM1
Muscle contraction	1	38.6×	0.035	STIM1
Hemostasis	1	18.0×	0.067	STIM1
Adaptive Immune System	1	14.9×	0.073	STIM1
Immune System	1	6.5×	0.148	STIM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of adenylate cyclase activity	2	3370.4×	1e-06	STIM1, ORAI1
store-operated calcium entry	2	1685.2×	3e-06	STIM1, ORAI1
regulation of calcium ion transport	2	802.5×	9e-06	STIM1, ORAI1
activation of store-operated calcium channel activity	1	1685.2×	0.003	STIM1
mammary gland epithelium development	1	936.2×	0.003	ORAI1
ligand-gated ion channel signaling pathway	1	936.2×	0.003	ORAI1
enamel mineralization	1	601.9×	0.004	STIM1
detection of calcium ion	1	561.7×	0.004	STIM1
regulation of store-operated calcium entry	1	526.6×	0.004	STIM1
calcium-ion regulated exocytosis	1	495.6×	0.004	ORAI1
calcineurin-NFAT signaling cascade	1	421.3×	0.004	ORAI1
calcium ion import	1	401.2×	0.004	ORAI1
positive regulation of calcium ion transport	1	290.6×	0.005	ORAI1
positive regulation of insulin secretion	1	127.7×	0.011	ORAI1
calcium ion transmembrane transport	1	105.3×	0.012	ORAI1
intracellular calcium ion homeostasis	1	72.6×	0.016	STIM1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.017	ORAI1
positive regulation of angiogenesis	1	57.7×	0.018	STIM1
adaptive immune response	1	42.1×	0.024	ORAI1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
STIM1	TERIFLUNOMIDE
ORAI1	MIBEFRADIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ORAI1	5	4
STIM1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TERIFLUNOMIDE	4	ORAI1, STIM1
MIBEFRADIL	4	ORAI1
ECONAZOLE	4	ORAI1
MICONAZOLE	4	ORAI1
ZEGOCRACTIN	2	ORAI1, STIM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ORAI1	59	Binding:57, Functional:1, ADMET:1
STIM1	35	Binding:33, Functional:1, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

5 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TERIFLUNOMIDE	4	ORAI1, STIM1
MIBEFRADIL	4	ORAI1
ECONAZOLE	4	ORAI1
MICONAZOLE	4	ORAI1
ZEGOCRACTIN	2	ORAI1, STIM1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	STIM1, ORAI1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.