Is VCP p.Arg159Ser (c.475C>A) pathogenic?

VCP p.Arg159Ser (c.475C>A) is classified Likely pathogenic in VCP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-23). AlphaMissense: likely pathogenic (0.9924); Absent from gnomAD v4.1; Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with VCP p.Arg159Ser (c.475C>A)?

VCP p.Arg159Ser (c.475C>A) is associated with amyotrophic lateral sclerosis type 6 (ClinVar).

How common is VCP p.Arg159Ser (c.475C>A) in the general population?

VCP p.Arg159Ser (c.475C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VCP p.Arg159Ser (c.475C>A)?

AlphaMissense predicts likely pathogenic (score 0.9924) — an in-silico prediction, not a clinical call.

VCP p.Arg159Ser

Q: How is Frontotemporal dementia with motor neuron disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.475C>A · rs387906789 · VCV989439

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9924 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
AlphaMissense	0.9924	likely pathogenic ✓ concordant with ClinVar
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -16.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.8, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 5,151 bp · p 1.5e-44 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VCP
Protein: p.Arg159Ser
Coding: c.475C>A
MANE Select: NM_007126
dbSNP: rs387906789
Type: single nucleotide variant
Location: chr9:35065352 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB
Residue 159: a β-strand; a UniProt-annotated variant site (in ftdals6); a UniProt-annotated variant site (in ibmpfd1; without frontotemporal dementia; abolishes enhancement of k-315 methylation by aspscr1)

Full VCP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amyotrophic lateral sclerosis type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

VCP p.Arg159Cys Pathogenic/Likely pathogenic ★★ same residue
VCP p.Arg159His Pathogenic ★★ same residue
VCP p.Arg159Gly Pathogenic same residue
VCP p.Arg155Cys Pathogenic/Likely pathogenic ★★ same type
VCP p.Arg155Gly Pathogenic/Likely pathogenic ★★ same type
VCP p.Arg155His Pathogenic ★★ ⚠ same type
VCP p.Arg191Gln Pathogenic/Likely pathogenic ★★ same type
VCP p.Arg191Pro Pathogenic/Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vcp-p-arg159ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown