# NM_007126.5(VCP):c.2149C>T (p.Pro717Ser)

https://sugi.bio/variant/vcp-p-pro717ser

## Summary

**VCP p.Pro717Ser (c.2149C>T)** is classified **Uncertain significance** in VCP (ClinVar, Single submitter, 2 submitters; last evaluated 2024-05-10). AlphaMissense: likely benign (0.2295); Very rare (popmax 8.47e-05%, nfe); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

**At a glance:** Uncertain significance · review: Single submitter · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the VCP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

*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 |
| Diagnostic panels | VCP is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Frontotemporal dementia with motor neuron disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal lower motor neuron morphology — Very frequent (99-80%)
- Abnormal upper motor neuron morphology — Very frequent (99-80%)
- Frontotemporal dementia — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Depression — Frequent (79-30%)
- Hallucinations — Frequent (79-30%)
- Apathy — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015733/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.Pro717Ser |
| Coding change (HGVS c.) | c.2149C>T |
| MANE Select transcript | [NM_007126](https://www.ncbi.nlm.nih.gov/nuccore/NM_007126) |
| Variant type | single nucleotide variant |
| Location | chr9:35059075-35059075 (GRCh38) |
| ClinVar | [VCV3354975](https://www.ncbi.nlm.nih.gov/clinvar/variation/3354975/) |

**All HGVS expressions:** `LRG_657:g.18668C>T`, `LRG_657t1:c.2149C>T`, `NC_000009.11:g.35059072G>A`, `NC_000009.12:g.35059075G>A`, `NG_007887.1:g.18668C>T`, `NM_001354927.2:c.2014C>T`, `NM_001354928.2:c.2014C>T`, `NM_007126.5:c.2149C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2295)
- REVEL 0.428 (indeterminate)
- SaProt LLR -7.234 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 8.505, GERP 1.8, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.5**. 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.*
- Regional missense constraint: **o/e 0.47** across the covering region of the MANE Select transcript (35,057,120–35,059,518), spanning 2,398 bp. Chi-square p 1.2e-13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for VCP (755 scored positions, the nearest 12 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,030 in the highest group · 4/1,613,860 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0101% | 9,867 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,180,030 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **717** lies in the 'disordered' region.

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. p.Pro717Ser falls in the disordered region. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-10.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-05-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-10 |

## Associated conditions {#conditions}

[frontotemporal dementia and/or amyotrophic lateral sclerosis 6](https://sugi.bio/atlas/disease/frontotemporal-dementia-and-or-amyotrophic-lateral-sclerosis-6/), [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/).

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

## Similar variants {#similar}

Related VCP variant pages (same residue, condition, or type): [VCP p.Pro717=](/variant/vcp-p-pro717), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3354975). 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.*