Is PEX6 p.Glu439fs (c.1313dup) pathogenic?

PEX6 p.Glu439fs (c.1313dup) is classified Pathogenic in PEX6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-25). Very rare (popmax 0.00223%, eas); Associated with Zellweger spectrum disorders.

What condition is associated with PEX6 p.Glu439fs (c.1313dup)?

PEX6 p.Glu439fs (c.1313dup) is associated with Zellweger spectrum disorders, peroxisome biogenesis disorder 4A (Zellweger), peroxisome biogenesis disorder 4B (ClinVar).

How common is PEX6 p.Glu439fs (c.1313dup) in the general population?

PEX6 p.Glu439fs (c.1313dup) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Zellweger syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PEX6 p.Glu439fs

c.1313dup · rs770055192 · VCV1323439

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.79	GERP -2.2, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,882 alleles

Overall 6.2e-05% 1/1,612,792 alleles · very rare exomes 0/1,460,654 · genomes 1/152,138 · 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: PEX6
Protein: p.Glu439fs
Coding: c.1313dup
MANE Select: NM_000287
dbSNP: rs770055192
Type: Duplication
Location: chr6:42969721 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.87

Full PEX6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Zellweger spectrum disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 4A (Zellweger)peroxisome biogenesis disorder 4B peroxisome biogenesis disorder

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PEX6 p.Glu290fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Gly171fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Gly473fs Pathogenic ★★ same condition
PEX6 p.Pro100fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Ser443fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Trp224fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Val525fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Gln965fs 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/pex6-p-glu439fs (accessed [today's date]).

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