Polyglucosan body myopathy 1 with or without immunodeficiency

Summary

Polyglucosan body myopathy 1 with or without immunodeficiency (MONDO:0014389) is a disease caused by RBCK1 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RBCK1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 514
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	polyglucosan body myopathy 1 with or without immunodeficiency
Mondo ID	MONDO:0014389
OMIM	615895
Orphanet	397937
UMLS	C4014605
MedGen	863042
GARD	0017643
Is cancer (heuristic)	no

Also known as: PGBM1 · polyglucosan body myopathy 1 with or without immunodeficiency · polyglucosan body myopathy type 1 · polyglucosan body myopathy, early-onset, with or without immunodeficiency

Data availability: 514 ClinVar variants · 3 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 › polyglucosan body myopathy › polyglucosan body myopathy 1 with or without immunodeficiency

Related subtypes (1): polyglucosan body myopathy type 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

514 retrieved; paginated sample, class counts are floors:

250 likely benign, 191 uncertain significance, 32 pathogenic, 18 benign, 7 likely pathogenic, 6 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070681	NM_031229.4(RBCK1):c.586_596del (p.Gly196fs)	RBCK1	Pathogenic	criteria provided, single submitter
1072347	NM_031229.4(RBCK1):c.949C>T (p.Gln317Ter)	RBCK1	Pathogenic	criteria provided, single submitter
1075761	NM_031229.4(RBCK1):c.663del (p.Glu222fs)	RBCK1	Pathogenic	criteria provided, single submitter
1163637	NM_031229.4(RBCK1):c.1258_1259dup (p.Arg421fs)	RBCK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184524	NM_031229.4(RBCK1):c.799C>T (p.Gln267Ter)	RBCK1	Pathogenic/Likely pathogenic	no assertion criteria provided
1184525	NM_031229.4(RBCK1):c.1522_1526del (p.Asn508fs)	RBCK1	Pathogenic/Likely pathogenic	no assertion criteria provided
1393408	NM_031229.4(RBCK1):c.751C>T (p.Gln251Ter)	RBCK1	Pathogenic	criteria provided, single submitter
140625	NM_031229.4(RBCK1):c.896_899del (p.Glu299fs)	RBCK1	Pathogenic	criteria provided, multiple submitters, no conflicts
140627	NM_031229.4(RBCK1):c.727G>T (p.Glu243Ter)	RBCK1	Pathogenic	no assertion criteria provided
140628	NM_031229.4(RBCK1):c.724_727dup (p.Glu243fs)	RBCK1	Pathogenic	criteria provided, multiple submitters, no conflicts
140629	NM_031229.4(RBCK1):c.790C>T (p.Gln264Ter)	RBCK1	Pathogenic	criteria provided, single submitter
140630	NM_031229.4(RBCK1):c.697_703dup (p.Glu235fs)	RBCK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686122	NM_031229.4(RBCK1):c.994_999del (p.Cys332_Ser333del)	RBCK1	Pathogenic	criteria provided, single submitter
1690386	NM_031229.4(RBCK1):c.745C>T (p.Gln249Ter)	RBCK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1998491	NM_031229.4(RBCK1):c.772C>T (p.Gln258Ter)	RBCK1	Pathogenic	criteria provided, single submitter
2029817	NM_031229.4(RBCK1):c.1111dup (p.Cys371fs)	RBCK1	Pathogenic	criteria provided, multiple submitters, no conflicts
2105689	NM_031229.4(RBCK1):c.49C>T (p.Arg17Ter)	RBCK1	Pathogenic	criteria provided, single submitter
2229016	NM_031229.4(RBCK1):c.748dup (p.Tyr250fs)	RBCK1	Pathogenic	criteria provided, multiple submitters, no conflicts
2703812	NM_031229.4(RBCK1):c.701_708dup (p.Ala238fs)	RBCK1	Pathogenic	criteria provided, single submitter
2706120	NM_031229.4(RBCK1):c.1386G>A (p.Trp462Ter)	RBCK1	Pathogenic	criteria provided, single submitter
2738369	NM_031229.4(RBCK1):c.1136G>A (p.Trp379Ter)	RBCK1	Pathogenic	criteria provided, single submitter
3248308	NC_000020.10:g.(?389402)(443049_?)del	RBCK1	Pathogenic	criteria provided, single submitter
3248309	NC_000020.10:g.(?389402)(398594_?)del	RBCK1	Pathogenic	criteria provided, single submitter
3248312	NC_000020.10:g.(?389402)(402902_?)del	RBCK1	Pathogenic	criteria provided, single submitter
3649308	NM_031229.4(RBCK1):c.1154dup (p.Asp385fs)	RBCK1	Pathogenic	criteria provided, single submitter
3724651	NM_031229.4(RBCK1):c.936_945del (p.Ile313fs)	RBCK1	Pathogenic	criteria provided, single submitter
4713986	NM_031229.4(RBCK1):c.1143_1144dup (p.Phe382fs)	RBCK1	Pathogenic	criteria provided, single submitter
4720630	NM_031229.4(RBCK1):c.716_717del (p.Arg239fs)	RBCK1	Pathogenic	criteria provided, single submitter
4725106	NM_031229.4(RBCK1):c.176_177dup (p.Ser60Ter)	RBCK1	Pathogenic	criteria provided, single submitter
4732433	NM_031229.4(RBCK1):c.1178dup (p.Cys394fs)	RBCK1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
RBCK1	Strong	Autosomal recessive	polyglucosan body myopathy 1 with or without immunodeficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RBCK1	Orphanet:329173	Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis
RBCK1	Orphanet:397937	Polyglucosan body myopathy type 1
RNF31	Orphanet:329173	Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis
CSNK2A1	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RBCK1	HGNC:15864	ENSG00000125826	Q9BYM8	RanBP-type and C3HC4-type zinc finger-containing protein 1	gencc,clinvar
RNF31	HGNC:16031	ENSG00000092098	Q96EP0	E3 ubiquitin-protein ligase RNF31	clinvar
CSNK2A1	HGNC:2457	ENSG00000101266	P68400	Casein kinase II subunit alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RBCK1	RanBP-type and C3HC4-type zinc finger-containing protein 1	E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates.
RNF31	E3 ubiquitin-protein ligase RNF31	E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear (‘Met-1’-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation.
CSNK2A1	Casein kinase II subunit alpha	Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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	2	5.5×	0.081
Kinase	1	9.2×	0.104

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RBCK1	Transcription factor	no		Ubiquitin-like_dom, Znf_RING, Znf_RanBP2
RNF31	Transcription factor	no	2.3.2.31	Znf_RanBP2, IBR_dom, Znf_RING/FYVE/PHD
CSNK2A1	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
apex of heart	1
granulocyte	1
spleen	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RBCK1	279	ubiquitous	marker	right hemisphere of cerebellum, adenohypophysis, cerebellar hemisphere
RNF31	134	ubiquitous	yes	spleen, granulocyte, apex of heart
CSNK2A1	301	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNF31	2,721
RBCK1	2,468
CSNK2A1	2,313

Intra-cohort edges

A	B	Sources
RBCK1	RNF31	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSNK2A1	P68400	320
RNF31	Q96EP0	36
RBCK1	Q9BYM8	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFR1-induced proapoptotic signaling	2	292.8×	3e-04	RBCK1, RNF31
TNFR1-induced NF-kappa-B signaling pathway	2	223.9×	3e-04	RBCK1, RNF31
Regulation of TNFR1 signaling	2	149.3×	4e-04	RBCK1, RNF31
Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK	1	761.3×	0.007	CSNK2A1
WNT mediated activation of DVL	1	475.8×	0.009	CSNK2A1
Condensation of Prometaphase Chromosomes	1	346.1×	0.009	CSNK2A1
Receptor Mediated Mitophagy	1	346.1×	0.009	CSNK2A1
Phosphorylation and nuclear translocation of the CRY:PER:kinase complex	1	271.9×	0.010	CSNK2A1
Maturation of hRSV A proteins	1	253.8×	0.010	CSNK2A1
Signal transduction by L1	1	173.0×	0.013	CSNK2A1
TNF signaling	1	141.0×	0.013	RNF31
Synthesis of PC	1	135.9×	0.013	CSNK2A1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	112.0×	0.015	CSNK2A1
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	100.2×	0.015	CSNK2A1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	100.2×	0.015	CSNK2A1
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	76.1×	0.018	CSNK2A1
Regulation of PTEN stability and activity	1	61.4×	0.021	CSNK2A1
Death Receptor Signaling	1	46.4×	0.026	RNF31
KEAP1-NFE2L2 pathway	1	40.1×	0.028	CSNK2A1
Regulation of TP53 Activity through Phosphorylation	1	39.2×	0.028	CSNK2A1
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.082	RBCK1
Signal Transduction	1	3.4×	0.267	RNF31

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein linear polyubiquitination	2	3744.9×	2e-06	RBCK1, RNF31
negative regulation of necroptotic process	2	660.9×	5e-05	RBCK1, RNF31
canonical NF-kappaB signal transduction	2	244.2×	3e-04	RBCK1, RNF31
obsolete positive regulation of NF-kappaB transcription factor activity	2	137.0×	6e-04	RBCK1, RNF31
negative regulation of canonical NF-kappaB signal transduction	2	114.6×	7e-04	RBCK1, RNF31
T cell receptor signaling pathway	2	101.2×	8e-04	RBCK1, RNF31
protein polyubiquitination	2	77.0×	0.001	RBCK1, RNF31
defense response to bacterium	2	72.0×	0.001	RBCK1, RNF31
regulation of chromosome separation	1	2808.7×	0.001	CSNK2A1
symbiont-mediated disruption of host cell PML body	1	1872.4×	0.002	CSNK2A1
positive regulation of canonical NF-kappaB signal transduction	2	48.4×	0.002	RBCK1, RNF31
positive regulation of aggrephagy	1	936.2×	0.003	CSNK2A1
positive regulation of xenophagy	1	702.2×	0.004	RNF31
CD40 signaling pathway	1	561.7×	0.005	RNF31
negative regulation of signal transduction by p53 class mediator	1	401.2×	0.006	CSNK2A1
negative regulation of double-strand break repair via homologous recombination	1	208.1×	0.011	CSNK2A1
negative regulation of apoptotic signaling pathway	1	187.2×	0.012	CSNK2A1
obsolete positive regulation of protein targeting to mitochondrion	1	165.2×	0.012	RNF31
positive regulation of extrinsic apoptotic signaling pathway	1	151.8×	0.013	RBCK1
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.014	CSNK2A1
positive regulation of Wnt signaling pathway	1	127.7×	0.014	CSNK2A1
obsolete negative regulation of NF-kappaB transcription factor activity	1	119.5×	0.014	RBCK1
positive regulation of non-canonical NF-kappaB signal transduction	1	85.1×	0.018	RBCK1
rhythmic process	1	83.8×	0.018	CSNK2A1
double-strand break repair	1	67.7×	0.021	CSNK2A1
positive regulation of protein catabolic process	1	67.7×	0.021	CSNK2A1
negative regulation of translation	1	65.3×	0.021	CSNK2A1
positive regulation of cell growth	1	61.1×	0.022	CSNK2A1
protein folding	1	34.5×	0.037	CSNK2A1
Wnt signaling pathway	1	33.2×	0.037	CSNK2A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
CSNK2A1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CSNK2A1	36	4
RBCK1	0	0
RNF31	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CSNK2A1
RUXOLITINIB	4	CSNK2A1
PALBOCICLIB	4	CSNK2A1
BELUMOSUDIL	4	CSNK2A1
ABEMACICLIB	4	CSNK2A1
NINTEDANIB	4	CSNK2A1
SUNITINIB	4	CSNK2A1
MIDOSTAURIN	4	CSNK2A1
MITOXANTRONE	4	CSNK2A1
QUERCETIN	3	CSNK2A1
LINIFANIB	3	CSNK2A1
ALISERTIB	3	CSNK2A1
DOVITINIB	3	CSNK2A1
LESTAURTINIB	3	CSNK2A1
RUBOXISTAURIN	3	CSNK2A1
ENTOSPLETINIB	3	CSNK2A1
SILMITASERTIB	2	CSNK2A1
FISETIN	2	CSNK2A1
ELLAGIC ACID	2	CSNK2A1
CI-1040	2	CSNK2A1
MOLIBRESIB	2	CSNK2A1
SU-014813	2	CSNK2A1
ONVANSERTIB	2	CSNK2A1
TG100-115	2	CSNK2A1
R-406	2	CSNK2A1
TOZASERTIB	2	CSNK2A1
LUTEOLIN	2	CSNK2A1
BAICALEIN	2	CSNK2A1
CHROMOCARB	2	CSNK2A1
PF-00562271	1	CSNK2A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CSNK2A1	1,085	Binding:937, Functional:146, ADMET:2
RNF31	2	Binding:2
RBCK1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNF31	2.3.2.31	RBR-type E3 ubiquitin transferase
CSNK2A1	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CSNK2A1	1,085

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
FEDRATINIB	4	CSNK2A1
RUXOLITINIB	4	CSNK2A1
PALBOCICLIB	4	CSNK2A1
BELUMOSUDIL	4	CSNK2A1
ABEMACICLIB	4	CSNK2A1
NINTEDANIB	4	CSNK2A1
SUNITINIB	4	CSNK2A1
MIDOSTAURIN	4	CSNK2A1
MITOXANTRONE	4	CSNK2A1
QUERCETIN	3	CSNK2A1
LINIFANIB	3	CSNK2A1
ALISERTIB	3	CSNK2A1
DOVITINIB	3	CSNK2A1
LESTAURTINIB	3	CSNK2A1
RUBOXISTAURIN	3	CSNK2A1
ENTOSPLETINIB	3	CSNK2A1
SILMITASERTIB	2	CSNK2A1
FISETIN	2	CSNK2A1
ELLAGIC ACID	2	CSNK2A1
CI-1040	2	CSNK2A1
MOLIBRESIB	2	CSNK2A1
SU-014813	2	CSNK2A1
ONVANSERTIB	2	CSNK2A1
TG100-115	2	CSNK2A1
R-406	2	CSNK2A1
TOZASERTIB	2	CSNK2A1
LUTEOLIN	2	CSNK2A1
BAICALEIN	2	CSNK2A1
CHROMOCARB	2	CSNK2A1
PF-00562271	1	CSNK2A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CSNK2A1
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	2	RBCK1, RNF31

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RBCK1	1	—
RNF31	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study