Is VAPB p.Pro35= (c.105G>A) pathogenic?

VAPB p.Pro35= (c.105G>A) is classified Benign/Likely benign in VAPB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-05). Ultra-rare (popmax 0.0747%, afr); Associated with amyotrophic lateral sclerosis type 8.

What condition is associated with VAPB p.Pro35= (c.105G>A)?

VAPB p.Pro35= (c.105G>A) is associated with amyotrophic lateral sclerosis type 8, adult-onset proximal spinal muscular atrophy, autosomal dominant (ClinVar).

How common is VAPB p.Pro35= (c.105G>A) in the general population?

VAPB p.Pro35= (c.105G>A) is ultra-rare (popmax 0.0747%, afr) (gnomAD).

VAPB p.Pro35=

c.105G>A · rs141383583 · VCV702264

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0747%, afr)

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 -3.3	GERP -5.6
Overall
CADD	7.225	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0747% African / African-American · 56/74,982 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0534%

Overall 0.00452% 73/1,614,038 alleles · ultra-rare exomes 40/1,461,882 · genomes 33/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0747%	1,339
Admixed American	0.0133%	7,502
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Remaining individualsnot grpmax-eligible	0.0032%	31,255
East Asian	0.00223%	44,884
South Asian	0.0022%	45,531
European (non-Finnish)	0.000169%	589,998

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.Pro35=
Coding: c.105G>A
MANE Select: NM_004738
dbSNP: rs141383583
Type: single nucleotide variant
Location: chr20:58418257 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 77.45 · 3 PDB
Residue 35: 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.Pro35Leu Uncertain significance ★ ⚠ same residue
VAPB p.Pro35Ser 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-pro35 (accessed [today's date]).

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