Is VAPB p.Ile233= (c.699C>T) pathogenic?

VAPB p.Ile233= (c.699C>T) is classified Likely benign in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). Very rare (popmax 0.00667%, amr); Associated with amyotrophic lateral sclerosis type 8.

What condition is associated with VAPB p.Ile233= (c.699C>T)?

VAPB p.Ile233= (c.699C>T) is associated with amyotrophic lateral sclerosis type 8, adult-onset proximal spinal muscular atrophy, autosomal dominant (ClinVar).

How common is VAPB p.Ile233= (c.699C>T) in the general population?

VAPB p.Ile233= (c.699C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

VAPB p.Ile233=

c.699C>T · rs372088559 · VCV1539617

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

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	<0.2	all four deltas below 0.2 · C>G here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.3	GERP -5.1
Overall
CADD	8.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,006 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000743% 12/1,614,046 alleles · very rare exomes 10/1,461,894 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
African / African-American	0.00267%	37,448
South Asian	0.0022%	45,544
European (non-Finnish)	0.000339%	295,010

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.Ile233=
Coding: c.699C>T
MANE Select: NM_004738
dbSNP: rs372088559
Type: single nucleotide variant
Location: chr20:58444202 (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

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-ile233 (accessed [today's date]).

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