Is PEX5 p.Pro42Arg (c.125C>G) pathogenic?

PEX5 p.Pro42Arg (c.125C>G) is classified Uncertain significance in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: likely benign (0.0842); Absent from gnomAD v4.1; Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Pro42Arg (c.125C>G)?

PEX5 p.Pro42Arg (c.125C>G) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Pro42Arg (c.125C>G) in the general population?

PEX5 p.Pro42Arg (c.125C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX5 p.Pro42Arg (c.125C>G)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

PEX5 p.Pro42Arg

c.125C>G · rs2539801040 · VCV1955982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.0842	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 1.3, phastCons 0.99
Overall
CADD	21.0	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: PEX5
Protein: p.Pro42Arg
Coding: c.125C>G
MANE Select: NM_001351132
dbSNP: rs2539801040
Type: single nucleotide variant
Location: chr12:7190502 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 42: the 'disordered' region

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.Pro42Ala Uncertain significance ★ ⚠ same residue
PEX5 p.Pro42Leu Uncertain significance ★ ⚠ same residue
PEX5 p.Pro42= 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

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-pro42arg (accessed [today's date]).

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