Is VAPB p.Ser158Arg (c.472A>C) pathogenic?

VAPB p.Ser158Arg (c.472A>C) is classified Uncertain significance in VAPB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-05). AlphaMissense: ambiguous (0.5149); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with VAPB p.Ser158Arg (c.472A>C)?

VAPB p.Ser158Arg (c.472A>C) is associated with Inborn genetic diseases, adult-onset proximal spinal muscular atrophy, autosomal dominant, amyotrophic lateral sclerosis type 8 (ClinVar).

How common is VAPB p.Ser158Arg (c.472A>C) in the general population?

VAPB p.Ser158Arg (c.472A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about VAPB p.Ser158Arg (c.472A>C)?

AlphaMissense predicts ambiguous (score 0.5149) — an in-silico prediction, not a clinical call.

VAPB p.Ser158Arg

c.472A>C · rs773800478 · VCV1388758

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5149	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -8.95	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP -0.44, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,319 bp · p 0.64 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,990 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,830 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,990
European (non-Finnish)	0.000254%	393,292

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.Ser158Arg
Coding: c.472A>C
MANE Select: NM_004738
dbSNP: rs773800478
Type: single nucleotide variant
Location: chr20:58440982 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 158: a modified residue (phosphoserine)

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-ser158arg (accessed [today's date]).

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