Myopathy, distal, with rimmed vacuoles

Summary

Myopathy, distal, with rimmed vacuoles (MONDO:0014945) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, distal, with rimmed vacuoles
Mondo ID	MONDO:0014945
OMIM	617158
DOID	DOID:0081363
UMLS	C5399975
MedGen	1728314
GARD	0016204
Is cancer (heuristic)	no

Also known as: DMRV · myopathy, distal, with rimmed vacuoles · myopathy, distal, with rimmed vacuoles; DMRV

Data availability: 14 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › muscular dystrophy › distal myopathy › myopathy, distal, with rimmed vacuoles

Related subtypes (10): myopathy, distal, infantile-onset, MYH7-related skeletal myopathy, Miyoshi myopathy, distal myopathy with anterior tibial onset, myopathy, distal, 5, autosomal dominant distal myopathy, nebulin-related early-onset distal myopathy, myopathy, distal, 7, adult-onset, X-linked, oculopharyngodistal myopathy, asymptomatic hyperckemia-myalgia-rhabdomyolysis syndrome

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

14 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 3 benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1458052	NM_003900.5(SQSTM1):c.1231G>A (p.Gly411Ser)	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8110	NM_003900.5(SQSTM1):c.1165+1G>A	SQSTM1	Pathogenic	criteria provided, single submitter
771810	NM_003900.5(SQSTM1):c.205+7G>C	LOC129995449	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2581000	NM_003900.5(SQSTM1):c.200A>G (p.Tyr67Cys)	LOC129995449	Uncertain significance	criteria provided, single submitter
3780664	NM_003900.5(SQSTM1):c.98C>A (p.Ala33Glu)	SQSTM1	Uncertain significance	criteria provided, single submitter
3892555	NM_003900.5(SQSTM1):c.223G>A (p.Val75Ile)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
542159	NM_003900.5(SQSTM1):c.970del	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
571746	NM_003900.5(SQSTM1):c.457G>A (p.Val153Ile)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
644285	NM_003900.5(SQSTM1):c.416G>A (p.Arg139His)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1248589	NM_003900.5(SQSTM1):c.755-23G>A	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
259189	NM_003900.5(SQSTM1):c.876C>T (p.Asp292=)	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
259191	NM_003900.5(SQSTM1):c.936G>A (p.Arg312=)	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
475410	NM_003900.5(SQSTM1):c.984G>A (p.Ser328=)	SQSTM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
542164	NM_003900.5(SQSTM1):c.1176G>A (p.Pro392=)	SQSTM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SQSTM1	7,269

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SQSTM1	Q13501	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
p75NTR signals via NF-kB	1	1903.3×	0.007	SQSTM1
Mitophagy	1	1038.2×	0.007	SQSTM1
Pexophagy	1	951.7×	0.007	SQSTM1
p75NTR recruits signalling complexes	1	878.5×	0.007	SQSTM1
NF-kB is activated and signals survival	1	878.5×	0.007	SQSTM1
NRIF signals cell death from the nucleus	1	713.8×	0.007	SQSTM1
PINK1-PRKN Mediated Mitophagy	1	356.9×	0.010	SQSTM1
Nuclear events mediated by NFE2L2	1	335.9×	0.010	SQSTM1
Selective autophagy	1	278.5×	0.010	SQSTM1
Interleukin-1 family signaling	1	271.9×	0.010	SQSTM1
Signaling by ALK in cancer	1	271.9×	0.010	SQSTM1
Cell death signalling via NRAGE, NRIF and NADE	1	219.6×	0.012	SQSTM1
p75 NTR receptor-mediated signalling	1	187.2×	0.013	SQSTM1
Signaling by ALK fusions and activated point mutants	1	150.3×	0.013	SQSTM1
Autophagy	1	148.3×	0.013	SQSTM1
Cellular response to chemical stress	1	142.8×	0.013	SQSTM1
Death Receptor Signaling	1	139.3×	0.013	SQSTM1
Interleukin-1 signaling	1	124.1×	0.013	SQSTM1
KEAP1-NFE2L2 pathway	1	120.2×	0.013	SQSTM1
Macroautophagy	1	115.3×	0.013	SQSTM1
Signaling by Interleukins	1	64.2×	0.023	SQSTM1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.025	SQSTM1
Neddylation	1	47.4×	0.028	SQSTM1
Cytokine Signaling in Immune system	1	40.8×	0.032	SQSTM1
Cellular responses to stress	1	36.8×	0.034	SQSTM1
Cellular responses to stimuli	1	31.5×	0.038	SQSTM1
Post-translational protein modification	1	19.2×	0.060	SQSTM1
Disease	1	13.1×	0.082	SQSTM1
Immune System	1	13.0×	0.082	SQSTM1
Metabolism of proteins	1	12.4×	0.084	SQSTM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
brown fat cell proliferation	1	5617.3×	0.003	SQSTM1
protein targeting to vacuole involved in autophagy	1	5617.3×	0.003	SQSTM1
response to mitochondrial depolarisation	1	2808.7×	0.004	SQSTM1
regulation of Ras protein signal transduction	1	1872.4×	0.004	SQSTM1
aggrephagy	1	1685.2×	0.004	SQSTM1
protein localization to perinuclear region of cytoplasm	1	1404.3×	0.004	SQSTM1
negative regulation of toll-like receptor 4 signaling pathway	1	1123.5×	0.004	SQSTM1
membraneless organelle assembly	1	1123.5×	0.004	SQSTM1
pexophagy	1	1053.2×	0.004	SQSTM1
regulation of protein complex stability	1	1053.2×	0.004	SQSTM1
regulation of mitochondrion organization	1	842.6×	0.004	SQSTM1
cellular response to stress	1	842.6×	0.004	SQSTM1
negative regulation of ferroptosis	1	802.5×	0.004	SQSTM1
autophagy of mitochondrion	1	732.7×	0.004	SQSTM1
positive regulation of long-term synaptic potentiation	1	674.1×	0.004	SQSTM1
temperature homeostasis	1	648.1×	0.004	SQSTM1
regulation of canonical NF-kappaB signal transduction	1	481.5×	0.005	SQSTM1
immune system process	1	391.9×	0.005	SQSTM1
endosome organization	1	374.5×	0.005	SQSTM1
mitophagy	1	318.0×	0.006	SQSTM1
negative regulation of protein ubiquitination	1	285.6×	0.006	SQSTM1
energy homeostasis	1	271.8×	0.006	SQSTM1
positive regulation of protein localization to plasma membrane	1	271.8×	0.006	SQSTM1
response to ischemia	1	251.5×	0.006	SQSTM1
endosomal transport	1	244.2×	0.006	SQSTM1
macroautophagy	1	240.7×	0.006	SQSTM1
protein catabolic process	1	237.3×	0.006	SQSTM1
positive regulation of autophagy	1	208.1×	0.007	SQSTM1
protein import into nucleus	1	144.0×	0.009	SQSTM1
autophagy	1	110.1×	0.012	SQSTM1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SQSTM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SQSTM1	20	Binding:20

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	SQSTM1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SQSTM1	20	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.