Is VAPB p.Leu125Met (c.373T>A) pathogenic?

VAPB p.Leu125Met (c.373T>A) is classified Uncertain significance in VAPB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely benign (0.1159); Very rare (popmax 0.00333%, amr); Associated with amyotrophic lateral sclerosis type 8.

What condition is associated with VAPB p.Leu125Met (c.373T>A)?

VAPB p.Leu125Met (c.373T>A) is associated with amyotrophic lateral sclerosis type 8, adult-onset proximal spinal muscular atrophy, autosomal dominant (ClinVar).

How common is VAPB p.Leu125Met (c.373T>A) in the general population?

VAPB p.Leu125Met (c.373T>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about VAPB p.Leu125Met (c.373T>A)?

AlphaMissense predicts likely benign (score 0.1159) — an in-silico prediction, not a clinical call.

VAPB p.Leu125Met

c.373T>A · rs755094802 · VCV2934872

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 8

Computational evidence

Protein change
AlphaMissense	0.1159	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -2, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 23 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	18.21	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000868% 14/1,613,808 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
African / African-American	0.00133%	74,946
European (non-Finnish)	0.000932%	107,271

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.Leu125Met
Coding: c.373T>A
MANE Select: NM_004738
dbSNP: rs755094802
Type: single nucleotide variant
Location: chr20:58439002 (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.Leu125= Likely benign ★ 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-leu125met (accessed [today's date]).

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