Is VCP p.Ala537= (c.1611C>G) pathogenic?

VCP p.Ala537= (c.1611C>G) is classified Likely benign in VCP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). Ultra-rare (popmax 0.0107%, afr); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 6.

What condition is associated with VCP p.Ala537= (c.1611C>G)?

VCP p.Ala537= (c.1611C>G) 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.Ala537= (c.1611C>G) in the general population?

VCP p.Ala537= (c.1611C>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

VCP p.Ala537=

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.1611C>G · rs750247487 · VCV1089780

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -0.5, phastCons 1
Overall
CADD	9.194	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,938 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000558% 9/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,367
European (non-Finnish)	8.47e-05%	1,180,059

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.Ala537=
Coding: c.1611C>G
MANE Select: NM_007126
dbSNP: rs750247487
Type: single nucleotide variant
Location: chr9:35060397 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB

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.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
VCP p.Arg256Gly 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-ala537 (accessed [today's date]).

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