# NM_007126.5(VCP):c.132C>G (p.Pro44=)

https://sugi.bio/variant/vcp-p-pro44

## Summary

**VCP p.Pro44= (c.132C>G)** is classified **Likely benign** in VCP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). Very rare (popmax 0.00667%, amr); Associated with inclusion body myopathy with Paget disease of bone and frontotemporal dementia.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 2 linked conditions · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the VCP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to inclusion body myopathy with Paget disease of bone and frontotemporal dementia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | VCP is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Inclusion body myopathy with Paget disease of bone and frontotemporal dementia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Distal muscle weakness — Very frequent (99-80%)
- Waddling gait — Very frequent (99-80%)
- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Hyperlordosis — Very frequent (99-80%)
- EMG: myopathic abnormalities — Very frequent (99-80%)
- Increased variability in muscle fiber diameter — Very frequent (99-80%)
- Proximal muscle weakness — Very frequent (99-80%)
- Rimmed vacuoles — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010899/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VCP](https://sugi.bio/atlas/gene/VCP/) |
| Protein change (HGVS p.) | p.Pro44= |
| Coding change (HGVS c.) | c.132C>G |
| MANE Select transcript | [NM_007126](https://www.ncbi.nlm.nih.gov/nuccore/NM_007126) |
| Variant type | single nucleotide variant |
| Location | chr9:35068061-35068061 (GRCh38) |
| ClinVar | [VCV4788738](https://www.ncbi.nlm.nih.gov/clinvar/variation/4788738/) |

**All HGVS expressions:** `LRG_657:g.9682C>G`, `LRG_657t1:c.132C>G`, `NC_000009.11:g.35068058G>C`, `NC_000009.12:g.35068061G>C`, `NG_007887.1:g.9682C>G`, `NM_001354927.2:c.-4C>G`, `NM_001354928.2:c.-4C>G`, `NM_007126.5:c.132C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 6.732, GERP 0.865, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.14**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/60,006 in the highest group · 6/1,614,082 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00667% | 15,002 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| European (non-Finnish) | 8.47e-05% | 1,180,057 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**VCP** population constraint: LOEUF 0.134, pLI 1, missense-Z 8.1717. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **inclusion body myopathy with Paget disease of bone and frontotemporal dementia** — Definitive (AD)

## Protein context {#protein}

Residue **44** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 83.11, 43% of residues very-high.

**144 experimental structure(s)** (PDB): [3EBB](https://www.rcsb.org/structure/3EBB), [3HU1](https://www.rcsb.org/structure/3HU1), [3HU2](https://www.rcsb.org/structure/3HU2), [3HU3](https://www.rcsb.org/structure/3HU3), [3QC8](https://www.rcsb.org/structure/3QC8), [3QQ7](https://www.rcsb.org/structure/3QQ7) — incl. mutant structure 3HU1.

## What this gene does {#gene-function}

*Describes the biological roles of VCP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** VCP's established molecular role includes RNA binding. In Reactome, VCP is annotated in disease pathway(s) including **Attachment and Entry**, **Defective CFTR causes cystic fibrosis**.

**Disease mechanism (Reactome):** VCP loss or alteration is curated in [Attachment and Entry](https://reactome.org/content/detail/R-HSA-9678110), [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895), [Dengue Virus Genome Translation and Replication](https://reactome.org/content/detail/R-HSA-9918487).

### Pathways affected {#pathways}

VCP participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Attachment and Entry](https://reactome.org/content/detail/R-HSA-9678110) | curated |
| ⚕ [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895) | curated |
| ⚕ [Dengue Virus Genome Translation and Replication](https://reactome.org/content/detail/R-HSA-9918487) | curated |
| ⚕ [Hh mutants are degraded by ERAD](https://reactome.org/content/detail/R-HSA-5362768) | curated |
| ⚕ [Attachment and Entry](https://reactome.org/content/detail/R-HSA-9694614) | electronic |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9931269) | curated |
| [E3 ubiquitin ligases ubiquitinate target proteins](https://reactome.org/content/detail/R-HSA-8866654) | curated |
| [HSF1 activation](https://reactome.org/content/detail/R-HSA-3371511) | curated |
| [Hedgehog ligand biogenesis](https://reactome.org/content/detail/R-HSA-5358346) | curated |
| [Josephin domain DUBs](https://reactome.org/content/detail/R-HSA-5689877) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [N-glycan trimming in the ER and Calnexin/Calreticulin cycle](https://reactome.org/content/detail/R-HSA-532668) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [Protein methylation](https://reactome.org/content/detail/R-HSA-8876725) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |
| [Translesion Synthesis by POLH](https://reactome.org/content/detail/R-HSA-110320) | curated |
| [Aggrephagy](https://reactome.org/content/detail/R-HSA-9646399) | electronic |
| [Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide](https://reactome.org/content/detail/R-HSA-9954709) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA binding, ATP hydrolysis activity, protein phosphatase binding, protein domain specific binding, polyubiquitin modification-dependent protein binding, ubiquitin protein ligase binding.

**Biological process:** mitophagy, double-strand break repair, autophagy, DNA damage response, proteasomal protein catabolic process, positive regulation of mitochondrial membrane potential.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-29.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-29 |

## Associated conditions {#conditions}

[inclusion body myopathy with Paget disease of bone and frontotemporal dementia](https://sugi.bio/atlas/disease/inclusion-body-myopathy-with-paget-disease-of-bone-and-frontotemporal-dementia/), [frontotemporal dementia and/or amyotrophic lateral sclerosis 6](https://sugi.bio/atlas/disease/frontotemporal-dementia-and-or-amyotrophic-lateral-sclerosis-6/).

**Reported phenotype names (ClinVar):** Inclusion body myopathy with Paget disease of bone and frontotemporal dementia, Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia, VCP-Related Amyotrophic Lateral Sclerosis, VCP-Related Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.

## Similar variants {#similar}

Related VCP variant pages (same residue, condition, or type): [VCP p.Arg155Cys](/variant/vcp-p-arg155cys), [VCP p.Arg155Gly](/variant/vcp-p-arg155gly), [VCP p.Arg155His](/variant/vcp-p-arg155his), [VCP p.Arg159Cys](/variant/vcp-p-arg159cys), [VCP p.Arg159His](/variant/vcp-p-arg159his), [VCP p.Arg191Gln](/variant/vcp-p-arg191gln), [VCP p.Arg191Pro](/variant/vcp-p-arg191pro), [VCP p.Arg256Gly](/variant/vcp-p-arg256gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4788738). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*