inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3

Summary

inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3 (MONDO:0014179) is a disease caused by HNRNPA1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: HNRNPA1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3
Mondo ID	MONDO:0014179
OMIM	615424
DOID	DOID:0111386
UMLS	C3809469
MedGen	815799
GARD	0015963
Is cancer (heuristic)	no

Also known as: HNRNPA1 inclusion body myopathy with Paget disease of bone and frontotemporal dementia · IBMPFD3 · inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3 · inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia type 3 · inclusion body myopathy with early-onset paget disease without frontotemporal dementia 3 · inclusion body myopathy with Paget disease of bone and frontotemporal dementia caused by mutation in HNRNPA1

Data availability: 6 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › inclusion body myopathy with Paget disease of bone and frontotemporal dementia › inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3

Related subtypes (3): inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1, inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, inclusion body myopathy and brain white matter abnormalities

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

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
637023	NM_031157.4(HNRNPA1):c.1018C>G (p.Pro340Ala)	HNRNPA1	Likely pathogenic	criteria provided, single submitter
65451	NM_031157.4(HNRNPA1):c.941A>T (p.Asp314Val)	HNRNPA1	Likely pathogenic	criteria provided, single submitter
1333611	NM_031157.4(HNRNPA1):c.240_243del (p.Asp80fs)	HNRNPA1	Uncertain significance	criteria provided, single submitter
1677313	NM_031157.4(HNRNPA1):c.1099G>A (p.Gly367Ser)	HNRNPA1	Uncertain significance	criteria provided, single submitter
2432495	NM_031157.4(HNRNPA1):c.959A>G (p.Asn320Ser)	HNRNPA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1209889	NM_031157.4(HNRNPA1):c.491-3dup	HNRNPA1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
HNRNPA1	Strong	Autosomal dominant	inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNRNPA1	Orphanet:399086	HNRNPA1-related adult-onset distal myopathy
HNRNPA1	Orphanet:52430	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
HNRNPA1	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
HNRNPA1	HGNC:5031	ENSG00000135486	P09651	Heterogeneous nuclear ribonucleoprotein A1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNRNPA1	Heterogeneous nuclear ribonucleoprotein A1	Involved in the packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and modulation of splice site selection.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNRNPA1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, HnRNPA1/A2_C

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
embryo	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNRNPA1	295	ubiquitous	marker	ganglionic eminence, ventricular zone, embryo

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNRNPA1	6,616

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HNRNPA1	P09651	73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
FGFR2 alternative splicing	1	423.0×	0.015	HNRNPA1
Signaling by FGFR2	1	407.9×	0.015	HNRNPA1
Signaling by FGFR	1	346.1×	0.015	HNRNPA1
SARS-CoV-1 modulates host translation machinery	1	308.6×	0.015	HNRNPA1
SARS-CoV-1-host interactions	1	175.7×	0.020	HNRNPA1
SARS-CoV-1 Infection	1	142.8×	0.021	HNRNPA1
mRNA Splicing	1	109.8×	0.023	HNRNPA1
mRNA Polyadenylation	1	87.8×	0.024	HNRNPA1
Processing of Capped Intron-Containing Pre-mRNA	1	82.2×	0.024	HNRNPA1
SARS-CoV Infections	1	55.4×	0.029	HNRNPA1
mRNA Splicing - Major Pathway	1	54.6×	0.029	HNRNPA1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.029	HNRNPA1
Dengue Virus-Host Interactions	1	45.7×	0.030	HNRNPA1
Metabolism of RNA	1	41.7×	0.031	HNRNPA1
Viral Infection Pathways	1	30.8×	0.039	HNRNPA1
Infectious disease	1	24.8×	0.045	HNRNPA1
Disease	1	13.1×	0.081	HNRNPA1
Signal Transduction	1	10.2×	0.098	HNRNPA1

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
cellular response to sodium arsenite	1	3370.4×	0.002	HNRNPA1
import into nucleus	1	2407.4×	0.002	HNRNPA1
nuclear export	1	1532.0×	0.003	HNRNPA1
RNA export from nucleus	1	936.2×	0.003	HNRNPA1
negative regulation of telomere maintenance via telomerase	1	732.7×	0.003	HNRNPA1
positive regulation of telomere maintenance via telomerase	1	732.7×	0.003	HNRNPA1
alternative mRNA splicing, via spliceosome	1	674.1×	0.003	HNRNPA1
cellular response to glucose starvation	1	337.0×	0.004	HNRNPA1
mRNA transport	1	263.3×	0.005	HNRNPA1
regulation of alternative mRNA splicing, via spliceosome	1	244.2×	0.005	HNRNPA1
regulation of RNA splicing	1	218.9×	0.005	HNRNPA1
mRNA splicing, via spliceosome	1	91.6×	0.011	HNRNPA1

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
HNRNPA1	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
HNRNPA1	7	Binding:7

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	HNRNPA1

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)
HNRNPA1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.