Myopathy, autophagic vacuolar, infantile-onset

Summary

Myopathy, autophagic vacuolar, infantile-onset (MONDO:0012286) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, autophagic vacuolar, infantile-onset
Mondo ID	MONDO:0012286
OMIM	609500
UMLS	C2931230
MedGen	419364
GARD	0024858
Is cancer (heuristic)	no

Also known as: myopathy, autophagic vacuolar, infantile-onset

Data availability: 5 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 › progressive muscular dystrophy › X-linked myopathy with excessive autophagy › myopathy, autophagic vacuolar, infantile-onset

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6030	NM_005476.7(GNE):c.737G>A (p.Arg246Gln)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
861130	NM_005476.7(GNE):c.2023T>C (p.Tyr675His)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709856	NM_014365.3(HSPB8):c.508_509del (p.Gln170fs)	HSPB8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233243	NM_001382567.1(STIM1):c.216C>A (p.His72Gln)	STIM1	Likely pathogenic	criteria provided, single submitter
2574645	NM_002137.4(HNRNPA2B1):c.996_997dup (p.Gly333fs)	HNRNPA2B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
GNE	Orphanet:3166	Sialuria
GNE	Orphanet:438207	Severe autosomal recessive macrothrombocytopenia
GNE	Orphanet:602	GNE myopathy
HSPB8	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB8	Orphanet:476093	HSPB8-related autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome
HSPB8	Orphanet:99945	Autosomal dominant Charcot-Marie-Tooth disease type 2L
HNRNPA2B1	Orphanet:52430	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STIM1	HGNC:11386	ENSG00000167323	Q13586	Stromal interaction molecule 1	clinvar
GNE	HGNC:23657	ENSG00000159921	Q9Y223	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	clinvar
HSPB8	HGNC:30171	ENSG00000152137	Q9UJY1	Heat shock protein beta-8	clinvar
HNRNPA2B1	HGNC:5033	ENSG00000122566	P22626	Heterogeneous nuclear ribonucleoproteins A2/B1	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.
GNE	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	Bifunctional enzyme that possesses both UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities, and serves as the initiator of the biosynthetic pathway leading to the production of N-acetylneuraminic acid (NeuAc), a…
HSPB8	Heat shock protein beta-8	Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle.
HNRNPA2B1	Heterogeneous nuclear ribonucleoproteins A2/B1	Heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with nascent pre-mRNAs, packaging them into hnRNP particles.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STIM1	Other/Unknown	no		SAM, SAM/pointed_sf, SOAR_STIM1/2
GNE	Enzyme (other)	yes	2.7.1.60	ROK, UDP_GlcNAc_Epimerase_2_dom, UDP-GlcNAc_Epase
HSPB8	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
HNRNPA2B1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, HnRNPA1/A2_C

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
hindlimb stylopod muscle	1
muscle of leg	1
colonic mucosa	1
mucosa of sigmoid colon	1
nasal cavity epithelium	1
mucosa of stomach	1
skeletal muscle tissue of rectus abdominis	1
epithelium of nasopharynx	1
tendon of biceps brachii	1
ventricular zone	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
GNE	286	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, nasal cavity epithelium
HSPB8	284	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, mucosa of stomach, gastrocnemius
HNRNPA2B1	295	ubiquitous	marker	epithelium of nasopharynx, tendon of biceps brachii, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNRNPA2B1	5,996
STIM1	3,074
GNE	2,210
HSPB8	1,916

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HNRNPA2B1	P22626	13
STIM1	Q13586	6
GNE	Q9Y223	5
HSPB8	Q9UJY1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GNE causes sialuria, NK and IBM2	1	2855.0×	0.009	GNE
Elevation of cytosolic Ca2+ levels	1	178.4×	0.032	STIM1
Platelet calcium homeostasis	1	178.4×	0.032	STIM1
Interleukin-12 family signaling	1	119.0×	0.032	HNRNPA2B1
Interleukin-12 signaling	1	102.0×	0.032	HNRNPA2B1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	89.2×	0.032	STIM1
Signaling by the B Cell Receptor (BCR)	1	86.5×	0.032	STIM1
Sialic acid metabolism	1	81.6×	0.032	GNE
HSF1-dependent transactivation	1	79.3×	0.032	HSPB8
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	75.1×	0.032	HNRNPA2B1
Platelet homeostasis	1	69.6×	0.032	STIM1
Ion homeostasis	1	51.0×	0.041	STIM1
mRNA Splicing	1	27.4×	0.060	HNRNPA2B1
Cardiac conduction	1	27.2×	0.060	STIM1
Immune System	2	6.5×	0.060	STIM1, HNRNPA2B1
mRNA Polyadenylation	1	22.0×	0.070	HNRNPA2B1
Processing of Capped Intron-Containing Pre-mRNA	1	20.5×	0.070	HNRNPA2B1
Muscle contraction	1	19.3×	0.071	STIM1
Signaling by Interleukins	1	16.0×	0.080	HNRNPA2B1
mRNA Splicing - Major Pathway	1	13.7×	0.089	HNRNPA2B1
Dengue Virus-Host Interactions	1	11.4×	0.101	HNRNPA2B1
Metabolism of RNA	1	10.4×	0.103	HNRNPA2B1
Cytokine Signaling in Immune system	1	10.2×	0.103	HNRNPA2B1
Hemostasis	1	9.0×	0.111	STIM1
Adaptive Immune System	1	7.5×	0.128	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
N-acetylglucosamine biosynthetic process	1	2106.5×	0.004	GNE
N-acetylneuraminate biosynthetic process	1	1404.3×	0.004	GNE
miRNA transport	1	1404.3×	0.004	HNRNPA2B1
activation of store-operated calcium channel activity	1	842.6×	0.004	STIM1
positive regulation of adenylate cyclase activity	1	842.6×	0.004	STIM1
UDP-N-acetylglucosamine metabolic process	1	702.2×	0.004	GNE
CMP-N-acetylneuraminate biosynthetic process	1	702.2×	0.004	GNE
positive regulation of telomere maintenance via telomere lengthening	1	702.2×	0.004	HNRNPA2B1
positive regulation of aggrephagy	1	702.2×	0.004	HSPB8
DNA geometric change	1	526.6×	0.005	HNRNPA2B1
store-operated calcium entry	1	421.3×	0.005	STIM1
RNA transport	1	383.0×	0.005	HNRNPA2B1
primary miRNA processing	1	324.1×	0.006	HNRNPA2B1
enamel mineralization	1	300.9×	0.006	STIM1
detection of calcium ion	1	280.9×	0.006	STIM1
regulation of store-operated calcium entry	1	263.3×	0.006	STIM1
cellular response to unfolded protein	1	247.8×	0.006	HSPB8
regulation of calcium ion transport	1	200.6×	0.007	STIM1
mRNA export from nucleus	1	73.9×	0.017	HNRNPA2B1
mRNA transport	1	65.8×	0.018	HNRNPA2B1
intracellular calcium ion homeostasis	1	36.3×	0.031	STIM1
positive regulation of angiogenesis	1	28.9×	0.037	STIM1
mRNA splicing, via spliceosome	1	22.9×	0.045	HNRNPA2B1
mRNA processing	1	19.7×	0.050	HNRNPA2B1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STIM1	2	4
GNE	0	0
HSPB8	0	0
HNRNPA2B1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TERIFLUNOMIDE	4	STIM1
ZEGOCRACTIN	2	STIM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
STIM1	35	Binding:33, Functional:1, ADMET:1
HNRNPA2B1	12	Binding:12
GNE	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GNE	2.7.1.60, 3.2.1.183, 5.1.3.14	N-acylmannosamine kinase, UDP-N-acetylglucosamine 2-epimerase (hydrolysing), UDP-N-acetylglucosamine 2-epimerase (non-hydrolysing)

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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	STIM1
ZEGOCRACTIN	2	STIM1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STIM1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GNE
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HSPB8, HNRNPA2B1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GNE	1	—
HSPB8	0	—
HNRNPA2B1	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.