Is PEX6 p.Ala447fs (c.1338_1339del) pathogenic?

PEX6 p.Ala447fs (c.13381339del) is classified Pathogenic/Likely pathogenic in PEX6 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-05-08). Very rare (popmax 0.00167%, amr); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Ala447fs (c.1338_1339del)?

PEX6 p.Ala447fs (c.1338_1339del) is associated with peroxisome biogenesis disorder, peroxisome biogenesis disorder 4A (Zellweger), peroxisome biogenesis disorder 4B (ClinVar).

How common is PEX6 p.Ala447fs (c.1338_1339del) in the general population?

PEX6 p.Ala447fs (c.1338_1339del) is very rare (popmax 0.00167%, amr) (gnomAD).

PEX6 p.Ala447fs

c.1338_1339del · rs398123303 · VCV92779

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

peroxisome biogenesis disorder

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 7.1	GERP 1.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,170 alleles · very rare exomes 3/1,460,886 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	0.000169%	590,005

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.Ala447fs
Coding: c.1338_1339del
MANE Select: NM_000287
dbSNP: rs398123303
Type: Microsatellite
Location: chr6:42969696 (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

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

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

Similar variants

PEX6 p.Ala447= Likely benign ★ same residue
PEX6 c.2364_2365del Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Cys167fs Likely pathogenic ★★ same condition
PEX6 p.Glu129fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Glu169fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Glu230fs Pathogenic ★★ same condition
PEX6 p.Glu320fs Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Glu366fs 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/pex6-p-ala447fs (accessed [today's date]).

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