Is PEX5 p.Pro488Thr (c.1462C>A) pathogenic?

PEX5 p.Pro488Thr (c.1462C>A) is classified Uncertain significance in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-22). AlphaMissense: ambiguous (0.5294); Absent from gnomAD v4.1; Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Pro488Thr (c.1462C>A)?

PEX5 p.Pro488Thr (c.1462C>A) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Pro488Thr (c.1462C>A) in the general population?

PEX5 p.Pro488Thr (c.1462C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX5 p.Pro488Thr (c.1462C>A)?

AlphaMissense predicts ambiguous (score 0.5294) — an in-silico prediction, not a clinical call.

PEX5 p.Pro488Thr

c.1462C>A · rs931591428 · VCV1713348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5294 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.5294	ambiguous
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -11.19	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 1
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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: PEX5
Protein: p.Pro488Thr
Coding: c.1462C>A
MANE Select: NM_001351132
dbSNP: rs931591428
Type: single nucleotide variant
Location: chr12:7209072 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 488: a UniProt-annotated variant site (in pbd2b; impaired ability to mediate peroxisomal import of proteins containing both a c-terminal pts1- and pts2-type targeting signals); an α-helix

Full PEX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX5 p.Pro488Ala Uncertain significance ★ ⚠ same residue
PEX5 p.Pro488= Likely benign ★ same residue
PEX5 c.449-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.552-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.847-2A>G Likely pathogenic ★★ same condition
PEX5 c.967-1G>A Likely pathogenic ★★ same condition
PEX5 p.Arg237Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg276Ter Pathogenic/Likely pathogenic ★★ 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/pex5-p-pro488thr (accessed [today's date]).

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