Is VAPB p.Ser146= (c.438A>G) pathogenic?

VAPB p.Ser146= (c.438A>G) is classified Likely benign in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-14). Very rare (popmax 0.00667%, afr); Associated with amyotrophic lateral sclerosis type 8.

What condition is associated with VAPB p.Ser146= (c.438A>G)?

VAPB p.Ser146= (c.438A>G) is associated with amyotrophic lateral sclerosis type 8, adult-onset proximal spinal muscular atrophy, autosomal dominant (ClinVar).

How common is VAPB p.Ser146= (c.438A>G) in the general population?

VAPB p.Ser146= (c.438A>G) is very rare (popmax 0.00667%, afr) (gnomAD).

VAPB p.Ser146=

c.438A>G · rs936346375 · VCV2937226

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Conditions

amyotrophic lateral sclerosis type 8

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 1.9	GERP -3.1, phastCons 1
Overall
CADD	8.138	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,936 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,613,972 alleles · very rare

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.Ser146=
Coding: c.438A>G
MANE Select: NM_004738
dbSNP: rs936346375
Type: single nucleotide variant
Location: chr20:58440948 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 146: a modified residue (phosphoserine)

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

Disease context

amyotrophic lateral sclerosis type 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: adult-onset proximal spinal muscular atrophy, autosomal dominant

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-ser146 (accessed [today's date]).

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