Is VCP p.Ala142= (c.426G>A) pathogenic?

VCP p.Ala142= (c.426G>A) is classified Conflicting classifications of pathogenicity in VCP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-02). Very rare (popmax 0.00439%, sas); Associated with inclusion body myopathy with Paget disease of bone and frontotemporal dementia.

What condition is associated with VCP p.Ala142= (c.426G>A)?

VCP p.Ala142= (c.426G>A) is associated with inclusion body myopathy with Paget disease of bone and frontotemporal dementia, frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (ClinVar).

How common is VCP p.Ala142= (c.426G>A) in the general population?

VCP p.Ala142= (c.426G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

VCP p.Ala142=

Q: How is Inclusion body myopathy with Paget disease of bone and frontotemporal dementia inherited?

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

c.426G>A · rs577812326 · VCV464109

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

inclusion body myopathy with Paget disease of bone and frontotemporal dementia

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 2.6	GERP -2, phastCons 1
Overall
CADD	14.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,074 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000496% 8/1,614,020 alleles · very rare exomes 7/1,461,854 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,769
Admixed American	0.00167%	59,990
European (non-Finnish)	0.000254%	393,331

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.Ala142=
Coding: c.426G>A
MANE Select: NM_007126
dbSNP: rs577812326
Type: single nucleotide variant
Location: chr9:35066694 (GRCh38)
Gene constraint: LOEUF 0.134 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 144 PDB
Residue 142: a turn

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

Disease context

inclusion body myopathy with Paget disease of bone and frontotemporal dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: frontotemporal dementia and/or amyotrophic lateral sclerosis 6

For Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

VCP p.Ala142Val Uncertain significance ★ ⚠ 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-ala142 (accessed [today's date]).

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