Is VAPB p.Pro111= (c.333G>A) pathogenic?

VAPB p.Pro111= (c.333G>A) is classified Likely benign in VAPB (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-11). Ultra-rare (popmax 0.0493%, mid); Associated with amyotrophic lateral sclerosis type 8.

What condition is associated with VAPB p.Pro111= (c.333G>A)?

VAPB p.Pro111= (c.333G>A) is associated with amyotrophic lateral sclerosis type 8, adult-onset proximal spinal muscular atrophy, autosomal dominant (ClinVar).

How common is VAPB p.Pro111= (c.333G>A) in the general population?

VAPB p.Pro111= (c.333G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

VAPB p.Pro111=

c.333G>A · rs762402998 · VCV772554

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

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 -2.3	GERP -5.6
Overall
CADD	8.826	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,080 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00322% 52/1,613,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
South Asian	0.00879%	11,382
Remaining individualsnot grpmax-eligible	0.0048%	20,823
Admixed American	0.00333%	29,996
European (non-Finnish)	0.00297%	33,712
African / African-American	0.00133%	74,908

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.Pro111=
Coding: c.333G>A
MANE Select: NM_004738
dbSNP: rs762402998
Type: single nucleotide variant
Location: chr20:58438962 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 111: a β-strand; the msp domain

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.Pro111Leu Conflicting classifications of pathogenicity ★ 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
VAPB p.Asp62Asn 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-pro111 (accessed [today's date]).

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