Is VPS53 p.Val125Met (c.373G>A) pathogenic?

VPS53 p.Val125Met (c.373G>A) is classified Uncertain significance in VPS53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 0.0011%, sas); Associated with pontocerebellar hypoplasia type 2E.

What condition is associated with VPS53 p.Val125Met (c.373G>A)?

VPS53 p.Val125Met (c.373G>A) is associated with pontocerebellar hypoplasia type 2E (ClinVar).

How common is VPS53 p.Val125Met (c.373G>A) in the general population?

VPS53 p.Val125Met (c.373G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about VPS53 p.Val125Met (c.373G>A)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

VPS53 p.Val125Met

c.373G>A · VCV4277906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pontocerebellar hypoplasia type 2E

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 2% in VPS53
REVEL	0.547	indeterminate
SaProt	LLR -13.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 196 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.0011% South Asian · 1/90,658 alleles

Overall 6.85e-05% 1/1,459,592 alleles · very rare

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: VPS53
Protein: p.Val125Met
Coding: c.373G>A
MANE Select: NM_001128159
Type: single nucleotide variant
Location: chr17:655953 (GRCh38)
Gene constraint: LOEUF 0.773 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.86

Full VPS53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pontocerebellar hypoplasia type 2E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VPS53 c.1556+5G>A Pathogenic/Likely pathogenic ★★ same condition
VPS53 p.Gln695Arg Pathogenic ★★ same condition
VPS53 p.Pro195Leu Uncertain significance ★★ same condition
VPS53 p.Pro416Gln Uncertain significance ★★ same condition
VPS53 c.1218+817A>G Benign ★★ same condition
VPS53 c.1867-71T>C Benign ★★ same condition
VPS53 c.1867-81C>T Benign ★★ same condition
VPS53 c.218+102C>G Benign ★★ 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/vps53-p-val125met (accessed [today's date]).

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