Is VAPB p.Arg223Pro (c.668G>C) pathogenic?

VAPB p.Arg223Pro (c.668G>C) is classified Uncertain significance in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-20). AlphaMissense: ambiguous (0.4434); Very rare (popmax 0.00769%, sas); Associated with adult-onset proximal spinal muscular atrophy, autosomal dominant.

How common is VAPB p.Arg223Pro (c.668G>C) in the general population?

VAPB p.Arg223Pro (c.668G>C) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about VAPB p.Arg223Pro (c.668G>C)?

AlphaMissense predicts ambiguous (score 0.4434) — an in-silico prediction, not a clinical call.

VAPB p.Arg223Pro

Q: What condition is associated with VAPB p.Arg223Pro (c.668G>C)?

VAPB p.Arg223Pro (c.668G>C) 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.668G>C · rs763755820 · VCV639834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Conditions

adult-onset proximal spinal muscular atrophy, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.4434	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -6.48	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,319 bp · p 0.64 · regional, not allelic
Overall
CADD	21.4	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 0.00769% South Asian · 7/91,082 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000434% 7/1,614,054 alleles · very rare exomes 5/1,461,894 · genomes 2/152,160 · joint denominator

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.Arg223Pro
Coding: c.668G>C
MANE Select: NM_004738
dbSNP: rs763755820
Type: single nucleotide variant
Location: chr20:58444171 (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.Arg223Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
VAPB p.Arg223Gln Uncertain significance ★ ⚠ same residue
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

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-arg223pro (accessed [today's date]).

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