Inclusion body myopathy with Paget disease of bone and frontotemporal dementia: genes and variants

Genes linked to Inclusion body myopathy with Paget disease of bone and frontotemporal dementia

• VCP: Transitional endoplasmic reticulum ATPase

  It uses ATP to extract ubiquitinated proteins from complexes or membranes for recycling or degradation and is central to proteostasis, ER-associated degradation, and autophagy. Dominant pathogenic variants cause multisystem proteinopathy with inclusion-body myopathy, Paget disease, frontotemporal dementia, or ALS.

  31 disease-causing and 138 uncertain variants in VCP are linked to Inclusion body myopathy with Paget disease of bone and frontotemporal dementia.

• HNRNPA1: Heterogeneous nuclear ribonucleoprotein A1

  It regulates pre-mRNA splicing, RNA transport, translation, and stress-granule dynamics through RNA binding and reversible self-assembly. Rare pathogenic variants can cause multisystem proteinopathy, amyotrophic lateral sclerosis, or related neuromuscular degeneration through altered RNA and protein homeostasis.

  0 disease-causing and 1 uncertain variants in HNRNPA1 are linked to Inclusion body myopathy with Paget disease of bone and frontotemporal dementia.

Known disease-causing variants in Inclusion body myopathy with Paget disease of bone and frontotemporal dementia

Uncertain variants in Inclusion body myopathy with Paget disease of bone and frontotemporal dementia that look disease-causing

Which prediction tools work for Inclusion body myopathy with Paget disease of bone and frontotemporal dementia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 75 out of 100

Same protein, different disease

• Childhood Onset VCP-related Neurodevelopmental Disorder is also caused by VCP variants; they fall mostly in different places as the Inclusion body myopathy with Paget disease of bone and frontotemporal dementia variants (4 disease-causing).

Diseases related to Inclusion body myopathy with Paget disease of bone and frontotemporal dementia

• Amyotrophic lateral sclerosis, also linked to HNRNPA1 and VCP
• Charcot-Marie-Tooth disease, also linked to VCP
• Alzheimer disease, also linked to VCP
• Frontotemporal dementia and/or amyotrophic lateral sclerosis, also linked to VCP
• Chronic progressive multiple sclerosis, also linked to HNRNPA1
• Childhood Onset VCP-related Neurodevelopmental Disorder, also linked to VCP
• Relapsing remitting multiple sclerosis, also linked to HNRNPA1
• Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3, also linked to HNRNPA1

Frequently asked questions

Which genes are linked to Inclusion body myopathy with Paget disease of bone and frontotemporal dementia?

In CATVariant, Inclusion body myopathy with Paget disease of bone and frontotemporal dementia is linked to 2 analyzed proteins: VCP (Transitional endoplasmic reticulum ATPase) and HNRNPA1 (Heterogeneous nuclear ribonucleoprotein A1).

How many genetic variants are linked to Inclusion body myopathy with Paget disease of bone and frontotemporal dementia?

177 variants: 31 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 139 are of uncertain significance or have conflicting reports.

Which uncertain variants in Inclusion body myopathy with Paget disease of bone and frontotemporal dementia look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example VCP R93H, VCP R89W and VCP P188L. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Inclusion body myopathy with Paget disease of bone and frontotemporal dementia?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.75, based on 31 disease-causing and 9 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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