PEX6

Chr 6ARAD

peroxisomal biogenesis factor 6

Also known as: HMLR2, PAF-2, PAF2, PBD4A, PDB4B, PXAAA1

NCBI Gene: 5190ENSG00000124587UniProt: Q13608

This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

Heimler syndrome 2MIM #616617
AR
Peroxisome biogenesis disorder 4A (Zellweger)MIM #614862
AR
Peroxisome biogenesis disorder 4BMIM #614863
ADAR
686
ClinVar variants
130
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PEX6
🧬
Gene-Disease Validity (ClinGen)
peroxisome biogenesis disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
130 Pathogenic / Likely Pathogenic· 203 VUS of 686 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.65LOEUF
pLI 0.000
Z-score 3.21
OE 0.42 (0.28–0.65)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.44Z-score
OE missense 0.82 (0.76–0.89)
436 obs / 529.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.42 (0.28–0.65)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.76–0.89)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 15 / 35.7Missense obs/exp: 436 / 529.4Syn Z: 0.36

ClinVar Variant Classifications

686 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic75
VUS203
Likely Benign351
Benign2
55
Pathogenic
75
Likely Pathogenic
203
VUS
351
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
26
4
25
0
55
Likely Pathogenic
51
3
21
0
75
VUS
1
174
21
7
203
Likely Benign
1
3
148
199
351
Benign
0
0
2
0
2
Total79184217206686

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PEX6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PEX6-related Heimler syndrome 2

moderate
ARUndeterminedAltered Gene Product Structure
SkinEar
G2P ↗

PEX6-related peroxisome biogenesis disorder 4B

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

PEX6-related peroxisome biogenesis disorder 4A (Zellweger)

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Heimler syndrome 2

MIM #616617

Molecular basis of disorder known

Autosomal recessive

Peroxisome biogenesis disorder 4A (Zellweger)

MIM #614862

Molecular basis of disorder known

Autosomal recessive

Peroxisome biogenesis disorder 4B

MIM #614863

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — PEX6
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Heimler Syndrome.
Mechaussier S et al.·Adv Exp Med Biol
2020Review
[Zellweger syndrome caused by PEX6 gene variation in 2 cases and literature review].
Yang P et al.·Zhonghua Er Ke Za Zhi
2024Review
A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder.
Galarreta CI et al.·Am J Med Genet A
2023
Dicarboxylic acylcarnitine biomarkers in peroxisome biogenesis disorders.
Wangler MF et al.·Mol Genet Metab
2023
Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders.
Suzuki Y et al.·J Inherit Metab Dis
2001Review
A novel splice variant in intron 10 of PEX6 is associated with Zellweger Syndrome in a Chinese neonate.
Yang P et al.·Gene
2024
Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.
Falkenberg KD et al.·Am J Hum Genet
2017
Expanding the clinical and genetic spectrum of Heimler syndrome.
Gao FJ et al.·Orphanet J Rare Dis
2019
Whole exome sequencing diagnosing syndromic and non-syndromic hearing loss with expansion of the phenotypic spectrum related to TMC1 variants.
Elbagoury NM et al.·Eur J Pediatr
2025
Heimler Syndrome With Tooth Agenesis, Abnormal Enamel and Dentin Mineralization, Root Maldevelopment, and PEX1 Mutation.
Kantaputra PN et al.·Int Dent J
2025Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools