peroxisome biogenesis disorder 2A (Zellweger)

Summary

peroxisome biogenesis disorder 2A (Zellweger) (MONDO:0008954) is a disease caused by PEX5 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PEX5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 125

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 2A (Zellweger)
Mondo ID	MONDO:0008954
OMIM	214110
DOID	DOID:0080477
UMLS	C3550273
MedGen	763187
GARD	0015149
Is cancer (heuristic)	no

Also known as: PBD2A · peroxisome biogenesis disorder 2A (Zellweger)

Data availability: 125 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › Zellweger spectrum disorders › peroxisome biogenesis disorder due to PEX5 defect › peroxisome biogenesis disorder 2A (Zellweger)

Related subtypes (1): peroxisome biogenesis disorder 2B

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

125 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 23 conflicting classifications of pathogenicity, 12 benign, 8 likely pathogenic, 7 likely benign, 4 pathogenic/likely pathogenic, 2 pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1453131	NM_001351132.2(PEX5):c.1258C>T (p.Arg420Ter)	PEX5	Pathogenic	criteria provided, multiple submitters, no conflicts
1699160	NM_001351132.2(PEX5):c.552G>A (p.Trp184Ter)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2177642	NM_001351132.2(PEX5):c.944_945dup (p.Thr316fs)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2978647	NM_001351132.2(PEX5):c.1578T>A (p.Asn526Lys)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9143	NM_001351132.2(PEX5):c.1578T>G (p.Asn526Lys)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9144	NM_001351132.2(PEX5):c.1279C>T (p.Arg427Ter)	PEX5	Pathogenic	criteria provided, multiple submitters, no conflicts
1471006	NM_001351132.2(PEX5):c.135_147+33delinsC	PEX5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582386	NM_001351132.2(PEX5):c.147+4A>G	PEX5	Likely pathogenic	criteria provided, single submitter
2794538	NM_001351132.2(PEX5):c.967-1G>A	PEX5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3575265	NM_001351132.2(PEX5):c.420_421inv (p.Trp140_Ser141delinsTer)	PEX5	Likely pathogenic	criteria provided, single submitter
3575267	NM_001351132.2(PEX5):c.1182_1183insATCAAACAGATCAAGC (p.Cys395fs)	PEX5	Likely pathogenic	criteria provided, single submitter
3575268	NM_001351132.2(PEX5):c.1296C>G (p.Tyr432Ter)	PEX5	Likely pathogenic	criteria provided, single submitter
3575269	NM_001351132.2(PEX5):c.1488_1510del (p.Val496_Leu497insTer)	PEX5	Likely pathogenic	criteria provided, single submitter
4294489	NM_001351132.2(PEX5):c.1182-1G>C	PEX5	Likely pathogenic	criteria provided, single submitter
194355	NM_001351132.2(PEX5):c.1413G>C (p.Val471=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283813	NM_001351132.2(PEX5):c.590C>T (p.Thr197Met)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287034	NM_001351132.2(PEX5):c.1707C>T (p.Leu569=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289541	NM_001351132.2(PEX5):c.604G>C (p.Val202Leu)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310417	NM_001351132.2(PEX5):c.498A>G (p.Gln166=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310420	NM_001351132.2(PEX5):c.552-7G>A	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310421	NM_001351132.2(PEX5):c.643-5C>T	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310422	NM_001351132.2(PEX5):c.754-4G>A	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310423	NM_001351132.2(PEX5):c.909T>C (p.Ala303=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310424	NM_001351132.2(PEX5):c.967-15G>A	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310425	NM_001351132.2(PEX5):c.1521C>T (p.Ala507=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310427	NM_001351132.2(PEX5):c.1559A>G (p.Asn520Ser)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310430	NM_001351132.2(PEX5):c.1653C>G (p.Leu551=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310431	NM_001351132.2(PEX5):c.1737T>C (p.Phe579=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310434	NM_001351132.2(PEX5):c.1875G>A (p.Ala625=)	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310438	NM_001351132.2(PEX5):c.*81A>C	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PEX5	Definitive	Autosomal recessive	peroxisome biogenesis disorder	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEX5	Orphanet:44	Neonatal adrenoleukodystrophy
PEX5	Orphanet:468717	Rhizomelic chondrodysplasia punctata type 5
PEX5	Orphanet:772	Infantile Refsum disease
PEX5	Orphanet:912	Zellweger syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PEX5	HGNC:9719	ENSG00000139197	P50542	Peroxisomal targeting signal 1 receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEX5	Peroxisomal targeting signal 1 receptor	Receptor that mediates peroxisomal import of proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX5	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, PEX5/PEX5L

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX5	142	ubiquitous	marker	gastrocnemius, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEX5	1,741

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PEX5	P50542	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Pexophagy	1	951.7×	0.003	PEX5
E3 ubiquitin ligases ubiquitinate target proteins	1	193.6×	0.006	PEX5
Peroxisomal protein import	1	173.0×	0.006	PEX5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein import into peroxisome matrix, docking	1	4213.0×	0.001	PEX5
protein import into peroxisome matrix, translocation	1	4213.0×	0.001	PEX5
protein import into peroxisome matrix, substrate release	1	3370.4×	0.001	PEX5
protein import into peroxisome membrane	1	2808.7×	0.001	PEX5
mitochondrial membrane organization	1	2407.4×	0.001	PEX5
protein import into peroxisome matrix, receptor recycling	1	2407.4×	0.001	PEX5
protein targeting to peroxisome	1	1685.2×	0.002	PEX5
cerebral cortex cell migration	1	1532.0×	0.002	PEX5
protein import into peroxisome matrix	1	1404.3×	0.002	PEX5
cerebral cortex neuron differentiation	1	1203.7×	0.002	PEX5
pexophagy	1	1053.2×	0.002	PEX5
cell development	1	887.0×	0.002	PEX5
very long-chain fatty acid metabolic process	1	766.0×	0.002	PEX5
protein tetramerization	1	624.1×	0.002	PEX5
neuromuscular process	1	526.6×	0.003	PEX5
positive regulation of multicellular organism growth	1	495.6×	0.003	PEX5
negative regulation of protein-containing complex assembly	1	455.5×	0.003	PEX5
endoplasmic reticulum organization	1	421.3×	0.003	PEX5
cellular response to reactive oxygen species	1	411.0×	0.003	PEX5
fatty acid beta-oxidation	1	374.5×	0.003	PEX5
neuron migration	1	133.8×	0.007	PEX5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PEX5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PEX5

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PEX5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.