Is VAPB p.Pro75Arg (c.224C>G) pathogenic?

VAPB p.Pro75Arg (c.224C>G) is classified Uncertain significance in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-19). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1; Associated with adult-onset proximal spinal muscular atrophy, autosomal dominant.

How common is VAPB p.Pro75Arg (c.224C>G) in the general population?

VAPB p.Pro75Arg (c.224C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VAPB p.Pro75Arg (c.224C>G)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

VAPB p.Pro75Arg

Q: What condition is associated with VAPB p.Pro75Arg (c.224C>G)?

VAPB p.Pro75Arg (c.224C>G) 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.224C>G · rs2123088879 · VCV1423442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adult-onset proximal spinal muscular atrophy, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic
REVEL	0.765	pathogenic-leaning
SaProt	LLR -16.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 23 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VAPB
Protein: p.Pro75Arg
Coding: c.224C>G
MANE Select: NM_004738
dbSNP: rs2123088879
Type: single nucleotide variant
Location: chr20:58434614 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 75: the msp domain

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-pro75arg (accessed [today's date]).

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