Is VCP p.Pro104Ser (c.310C>T) pathogenic?

VCP p.Pro104Ser (c.310C>T) is classified Uncertain significance in VCP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely benign (0.1587); Very rare (popmax 0.00167%, amr); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

What condition is associated with VCP p.Pro104Ser (c.310C>T)?

VCP p.Pro104Ser (c.310C>T) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6, inclusion body myopathy with Paget disease of bone and frontotemporal dementia (ClinVar).

How common is VCP p.Pro104Ser (c.310C>T) in the general population?

VCP p.Pro104Ser (c.310C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about VCP p.Pro104Ser (c.310C>T)?

AlphaMissense predicts likely benign (score 0.1587) — an in-silico prediction, not a clinical call.

VCP p.Pro104Ser

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.310C>T · rs1186937475 · VCV1357446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Computational evidence

Protein change
AlphaMissense	0.1587	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 5,547 bp · p 3e-08 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,024 alleles

Overall 0.000124% 2/1,614,132 alleles · very rare exomes 2/1,461,820 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,024
African / African-American	0.00133%	75,060

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VCP
Protein: p.Pro104Ser
Coding: c.310C>T
MANE Select: NM_007126
dbSNP: rs1186937475
Type: single nucleotide variant
Location: chr9:35066810 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB
Residue 104: a β-strand

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

Disease context

frontotemporal dementia and/or amyotrophic lateral sclerosis 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inclusion body myopathy with Paget disease of bone and frontotemporal dementia

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

VCP p.Pro104= Likely benign ★ same residue
VCP p.Arg155Cys Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg155Gly Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg155His Pathogenic ★★ ⚠ same condition
VCP p.Arg159Cys Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg159His Pathogenic ★★ same condition
VCP p.Arg191Gln Pathogenic/Likely pathogenic ★★ same condition
VCP p.Arg191Pro Pathogenic/Likely pathogenic ★★ same condition

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-pro104ser (accessed [today's date]).

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