Is PEX5 p.Ala422fs (c.1264dup) pathogenic?

PEX5 p.Ala422fs (c.1264dup) is classified Pathogenic in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). Very rare (popmax 8.47e-05%, nfe); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Ala422fs (c.1264dup)?

PEX5 p.Ala422fs (c.1264dup) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Ala422fs (c.1264dup) in the general population?

PEX5 p.Ala422fs (c.1264dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

PEX5 p.Ala422fs

c.1264dup · rs1374334296 · VCV1459320

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,960 alleles

Overall 6.2e-05% 1/1,614,150 alleles · very rare exomes 1/1,461,800 · genomes 0/152,350 · joint denominator

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: PEX5
Protein: p.Ala422fs
Coding: c.1264dup
MANE Select: NM_001351132
dbSNP: rs1374334296
Type: Duplication
Location: chr12:7208537 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 422: 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.Ala422Val Uncertain significance ★ ⚠ same residue
PEX5 p.Ala422= Likely benign ★ same residue
PEX5 p.Ser235fs Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Thr316fs Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.967-3dup Uncertain significance ★★ same condition
PEX5 c.1718+11_1718+14dup Likely benign ★★ same condition
PEX5 p.Arg427fs Pathogenic ★ same condition
PEX5 p.Leu270fs 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-ala422fs (accessed [today's date]).

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