Is VAPB p.Lys155= (c.465G>A) pathogenic?

VAPB p.Lys155= (c.465G>A) is classified Likely benign in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-27). Ultra-rare (popmax 0.0401%, eas); Associated with adult-onset proximal spinal muscular atrophy, autosomal dominant.

How common is VAPB p.Lys155= (c.465G>A) in the general population?

VAPB p.Lys155= (c.465G>A) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

VAPB p.Lys155=

Q: What condition is associated with VAPB p.Lys155= (c.465G>A)?

VAPB p.Lys155= (c.465G>A) is associated with adult-onset proximal spinal muscular atrophy, autosomal dominant, amyotrophic lateral sclerosis type 8 (ClinVar).

Q: How is Autosomal dominant adult-onset proximal spinal muscular atrophy inherited?

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

c.465G>A · rs779988555 · VCV1144418

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Conditions

adult-onset proximal spinal muscular atrophy, autosomal dominant

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 0.95	GERP -5, phastCons 0.027
Overall
CADD	3.326	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0401% East Asian · 18/44,854 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00149% 24/1,614,088 alleles · ultra-rare exomes 20/1,461,830 · genomes 4/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,492
South Asian	0.00439%	22,771
Admixed American	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,180,006

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: VAPB
Protein: p.Lys155=
Coding: c.465G>A
MANE Select: NM_004738
dbSNP: rs779988555
Type: single nucleotide variant
Location: chr20:58440975 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB

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

Disease context

adult-onset proximal spinal muscular atrophy, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 8

For Autosomal dominant adult-onset proximal spinal muscular atrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

VAPB p.Pro56Ser Pathogenic ★★ same condition
VAPB p.Ala104Thr Uncertain significance ★★ ⚠ same condition
VAPB p.Arg182Lys Uncertain significance ★★ ⚠ same condition
VAPB p.Asp163Asn Uncertain significance ★★ ⚠ same condition
VAPB p.Asp24Asn Uncertain significance ★★ ⚠ same condition
VAPB p.Asp37Glu Uncertain significance ★★ ⚠ same condition
VAPB p.Asp62Asn Uncertain significance ★★ ⚠ same condition
VAPB p.Asp77Asn Uncertain significance ★★ ⚠ 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/vapb-p-lys155 (accessed [today's date]).

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