Is VAPB p.Ser58= (c.174C>T) pathogenic?

VAPB p.Ser58= (c.174C>T) is classified Likely benign in VAPB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-15). Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

How common is VAPB p.Ser58= (c.174C>T) in the general population?

VAPB p.Ser58= (c.174C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

VAPB p.Ser58=

Q: What condition is associated with VAPB p.Ser58= (c.174C>T)?

VAPB p.Ser58= (c.174C>T) is associated with Inborn genetic diseases, adult-onset proximal spinal muscular atrophy, autosomal dominant, amyotrophic lateral sclerosis type 8 (ClinVar).

c.174C>T · rs139149560 · VCV534274

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Conditions

Inborn genetic diseases

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 -1.2	GERP -5.6, phastCons 0.002
Overall
CADD	9.647	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/75,008 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00452% 73/1,614,136 alleles · ultra-rare exomes 53/1,461,880 · genomes 20/152,256 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,412
South Asian	0.0209%	4,794
East Asian	0.0201%	4,987
Remaining individualsnot grpmax-eligible	0.0112%	8,930
European (non-Finnish)	0.00178%	56,192

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.Ser58=
Coding: c.174C>T
MANE Select: NM_004738
dbSNP: rs139149560
Type: single nucleotide variant
Location: chr20:58418326 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 58: a β-strand; the msp domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: adult-onset proximal spinal muscular atrophy, autosomal dominant amyotrophic lateral sclerosis type 8

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-ser58 (accessed [today's date]).

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