Is VPS53 p.Pro459Ser (c.1375C>T) pathogenic?

VPS53 p.Pro459Ser (c.1375C>T) is classified Uncertain significance in VPS53 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely benign (0.0854); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with VPS53 p.Pro459Ser (c.1375C>T)?

VPS53 p.Pro459Ser (c.1375C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VPS53 p.Pro459Ser (c.1375C>T) in the general population?

VPS53 p.Pro459Ser (c.1375C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VPS53 p.Pro459Ser (c.1375C>T)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

VPS53 p.Pro459Ser

c.1375C>T · rs2543722284 · VCV2302198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.52	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 8.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 196 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	22.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VPS53
Protein: p.Pro459Ser
Coding: c.1375C>T
MANE Select: NM_001128159
dbSNP: rs2543722284
Type: single nucleotide variant
Location: chr17:562684 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VPS53 p.Ala222Thr Uncertain significance ★★ ⚠ same condition
VPS53 p.Ala412Thr Uncertain significance ★★ ⚠ same condition
VPS53 p.Arg140Cys Uncertain significance ★★ ⚠ same condition
VPS53 p.Arg333Cys Uncertain significance ★★ ⚠ same condition
VPS53 p.Asp462Asn Uncertain significance ★★ ⚠ same condition
VPS53 p.Gly233Glu Uncertain significance ★★ ⚠ same condition
VPS53 p.Gly303Ser Uncertain significance ★★ ⚠ same condition
VPS53 p.Ile500Thr 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/vps53-p-pro459ser (accessed [today's date]).

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