peroxisome biogenesis disorder 2B

Summary

peroxisome biogenesis disorder 2B (MONDO:0008736) is a disease caused by PEX5 (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: PEX5 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 919

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 2B
Mondo ID	MONDO:0008736
OMIM	202370
DOID	DOID:0080622
NCIT	C155751
UMLS	C3550234
MedGen	763148
GARD	0015134
Is cancer (heuristic)	no

Also known as: PBD2B · peroxisome biogenesis disorder 2B · peroxisome biogenesis disorder type 2B

Data availability: 919 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

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 2B

Related subtypes (1): peroxisome biogenesis disorder 2A (Zellweger)

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

600 retrieved; paginated sample, class counts are floors:

281 likely benign, 262 uncertain significance, 27 pathogenic, 11 likely pathogenic, 7 conflicting classifications of pathogenicity, 7 benign, 4 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070685	NM_001351132.2(PEX5):c.1521_1527del (p.Val508fs)	PEX5	Pathogenic	criteria provided, single submitter
1072376	NM_001351132.2(PEX5):c.1469_1470insAC (p.Gln491fs)	PEX5	Pathogenic	criteria provided, single submitter
1074777	NM_001351132.2(PEX5):c.531_534dup (p.Thr179fs)	PEX5	Pathogenic	criteria provided, single submitter
1180670	NM_001351132.2(PEX5):c.674_695dup (p.Ser235fs)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362943	NM_001351132.2(PEX5):c.808dup (p.Leu270fs)	PEX5	Pathogenic	criteria provided, single submitter
1418378	NM_001351132.2(PEX5):c.1574G>A (p.Trp525Ter)	PEX5	Pathogenic	criteria provided, single submitter
1453131	NM_001351132.2(PEX5):c.1258C>T (p.Arg420Ter)	PEX5	Pathogenic	criteria provided, multiple submitters, no conflicts
1454762	NM_001351132.2(PEX5):c.119G>A (p.Trp40Ter)	PEX5	Pathogenic	criteria provided, single submitter
1456774	NM_001351132.2(PEX5):c.1255C>T (p.Gln419Ter)	PEX5	Pathogenic	criteria provided, single submitter
1458895	NM_001351132.2(PEX5):c.472del (p.Arg158fs)	PEX5	Pathogenic	criteria provided, single submitter
1459320	NM_001351132.2(PEX5):c.1264dup (p.Ala422fs)	PEX5	Pathogenic	criteria provided, single submitter
1459850	NM_001351132.2(PEX5):c.583C>T (p.Gln195Ter)	PEX5	Pathogenic	criteria provided, single submitter
1699160	NM_001351132.2(PEX5):c.552G>A (p.Trp184Ter)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999550	NM_001351132.2(PEX5):c.416_419del (p.Asp139fs)	PEX5	Pathogenic	criteria provided, single submitter
2007445	NM_001351132.2(PEX5):c.500C>G (p.Ser167Ter)	PEX5	Pathogenic	criteria provided, single submitter
2034747	NM_001351132.2(PEX5):c.76C>T (p.Gln26Ter)	PEX5	Pathogenic	criteria provided, single submitter
2055270	NM_001351132.2(PEX5):c.1355_1356del (p.Leu452fs)	PEX5	Pathogenic	criteria provided, single submitter
2082711	NM_001351132.2(PEX5):c.54_69dup (p.Phe24fs)	PEX5	Pathogenic	criteria provided, single submitter
2088202	NM_001351132.2(PEX5):c.1319_1320del (p.Val440fs)	PEX5	Pathogenic	criteria provided, single submitter
2137295	NM_001351132.2(PEX5):c.826C>T (p.Arg276Ter)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2147984	NM_001351132.2(PEX5):c.737_738del (p.Glu246fs)	PEX5	Pathogenic	criteria provided, single submitter
2177642	NM_001351132.2(PEX5):c.944_945dup (p.Thr316fs)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2710496	NM_001351132.2(PEX5):c.88del (p.Leu30fs)	PEX5	Pathogenic	criteria provided, single submitter
2711278	NM_001351132.2(PEX5):c.715C>T (p.Gln239Ter)	PEX5	Pathogenic	criteria provided, single submitter
2736808	NM_001351132.2(PEX5):c.82_83insT (p.Lys28fs)	PEX5	Pathogenic	criteria provided, single submitter
2746765	NM_001351132.2(PEX5):c.1607del (p.Asn536fs)	PEX5	Pathogenic	criteria provided, single submitter
2749134	NM_001351132.2(PEX5):c.1426del (p.Leu476fs)	PEX5	Pathogenic	criteria provided, single submitter
2757117	NM_001351132.2(PEX5):c.30del (p.Glu10fs)	PEX5	Pathogenic	criteria provided, single submitter
2769358	NM_001351132.2(PEX5):c.555T>A (p.Tyr185Ter)	PEX5	Pathogenic	criteria provided, single submitter
2769438	NM_001351132.2(PEX5):c.1279dup (p.Arg427fs)	PEX5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 13 · 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
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease
PEX6	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome
PEX6	Orphanet:44	Neonatal adrenoleukodystrophy
PEX6	Orphanet:772	Infantile Refsum disease
PEX6	Orphanet:912	Zellweger syndrome
PEX6	Orphanet:95433	Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PEX5	HGNC:9719	ENSG00000139197	P50542	Peroxisomal targeting signal 1 receptor	gencc,clinvar
ACRBP	HGNC:17195	ENSG00000111644	Q8NEB7	Acrosin-binding protein	clinvar
A2ML1	HGNC:23336	ENSG00000166535	A8K2U0	Alpha-2-macroglobulin-like protein 1	clinvar
ACSM4	HGNC:32016	ENSG00000215009	P0C7M7	Acyl-coenzyme A synthetase ACSM4, mitochondrial	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	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).
ACRBP	Acrosin-binding protein	Acrosomal protein that maintains proacrosin (pro-ACR) as an enzymatically inactive zymogen in the acrosome.
A2ML1	Alpha-2-macroglobulin-like protein 1	Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.
ACSM4	Acyl-coenzyme A synthetase ACSM4, mitochondrial	Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

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
Complement	1	44.7×	0.089
Transporter	1	13.0×	0.149
Enzyme (other)	1	2.0×	0.543
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX5	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, PEX5/PEX5L
ACRBP	Other/Unknown	no		Proacrosin-bd, Kazal_dom_sf
A2ML1	Complement	yes		Macroglobln_a2, MG2, Terpenoid_cyclase/PrenylTrfase
ACSM4	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS

Expression context

Cohort genes with no expression data: 0.

6 cohort genes 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
right testis	2
gastrocnemius	1
monocyte	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
right ovary	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
body of pancreas	1
mucosa of transverse colon	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX5	142	ubiquitous	marker	gastrocnemius, left testis, right testis
ACRBP	177	broad	marker	left testis, right testis, monocyte
A2ML1	176	tissue_specific	marker	lower esophagus mucosa, gingiva, gingival epithelium
ACSM4	82		marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right ovary
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
PEX6	227	ubiquitous	marker	right uterine tube, body of pancreas, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEX6	2,620
PEX5	1,741
ACSM4	1,566
ABCD1	1,181
A2ML1	1,128
ACRBP	1,029

Intra-cohort edges

A	B	Sources
PEX5	PEX6	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14
PEX5	P50542	11
A2ML1	A8K2U0	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSM4	P0C7M7	89.38
PEX6	Q13608	69.87
ACRBP	Q8NEB7	64.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Peroxisomal protein import	2	86.5×	0.005	PEX5, PEX6
Defective ABCD1 causes ALD	1	1427.5×	0.009	ABCD1
Amino Acid conjugation	1	571.0×	0.013	ACSM4
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	475.8×	0.013	ABCD1
Conjugation of salicylate with glycine	1	356.9×	0.013	ACSM4
Conjugation of carboxylic acids	1	317.2×	0.013	ACSM4
Linoleic acid (LA) metabolism	1	285.5×	0.013	ABCD1
Pexophagy	1	237.9×	0.014	PEX5
Beta-oxidation of very long chain fatty acids	1	219.6×	0.014	ABCD1
alpha-linolenic acid (ALA) metabolism	1	178.4×	0.015	ABCD1
Peroxisomal lipid metabolism	1	167.9×	0.015	ABCD1
ABC transporters in lipid homeostasis	1	150.3×	0.015	ABCD1
Class I peroxisomal membrane protein import	1	129.8×	0.016	ABCD1
ABC transporter disorders	1	109.8×	0.018	ABCD1
Aspirin ADME	1	79.3×	0.023	ACSM4
Phase II - Conjugation of compounds	1	69.6×	0.024	ACSM4
Drug ADME	1	57.1×	0.028	ACSM4
E3 ubiquitin ligases ubiquitinate target proteins	1	48.4×	0.030	PEX5
Protein localization	1	47.6×	0.030	ABCD1
Disorders of transmembrane transporters	1	34.8×	0.037	ABCD1
Fatty acid metabolism	1	32.8×	0.037	ABCD1
Biological oxidations	1	32.4×	0.037	ACSM4
ABC-family protein mediated transport	1	30.4×	0.038	ABCD1
Metabolism	2	5.8×	0.044	ACSM4, ABCD1
Metabolism of lipids	1	7.9×	0.131	ABCD1
Transport of small molecules	1	6.3×	0.156	ABCD1
Disease	1	3.3×	0.273	ABCD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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, translocation	2	1404.3×	3e-05	PEX5, PEX6
protein import into peroxisome matrix, receptor recycling	2	802.5×	6e-05	PEX5, PEX6
protein targeting to peroxisome	2	561.7×	8e-05	PEX5, PEX6
protein import into peroxisome matrix	2	468.1×	9e-05	PEX5, PEX6
peroxisome organization	2	267.5×	2e-04	ABCD1, PEX6
very long-chain fatty acid metabolic process	2	255.3×	2e-04	PEX5, ABCD1
fatty acid beta-oxidation	2	124.8×	8e-04	PEX5, ABCD1
regulation of endopeptidase activity	1	2808.7×	0.002	A2ML1
peroxisomal membrane transport	1	1404.3×	0.004	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	1404.3×	0.004	ABCD1
positive regulation of unsaturated fatty acid biosynthetic process	1	936.2×	0.005	ABCD1
protein import into peroxisome matrix, docking	1	702.2×	0.005	PEX5
sterol homeostasis	1	702.2×	0.005	ABCD1
long-chain fatty acid import into peroxisome	1	561.7×	0.005	ABCD1
protein unfolding	1	561.7×	0.005	PEX6
protein import into peroxisome matrix, substrate release	1	561.7×	0.005	PEX5
regulation of fatty acid beta-oxidation	1	468.1×	0.005	ABCD1
long-chain fatty acid catabolic process	1	468.1×	0.005	ABCD1
myelin maintenance	1	468.1×	0.005	ABCD1
protein import into peroxisome membrane	1	468.1×	0.005	PEX5
regulation of mitochondrial depolarization	1	468.1×	0.005	ABCD1
mitochondrial membrane organization	1	401.2×	0.005	PEX5
fatty acid elongation	1	401.2×	0.005	ABCD1
very long-chain fatty acid catabolic process	1	401.2×	0.005	ABCD1
cerebral cortex cell migration	1	255.3×	0.008	PEX5
positive regulation of fatty acid beta-oxidation	1	255.3×	0.008	ABCD1
fatty acid derivative biosynthetic process	1	255.3×	0.008	ABCD1
regulation of cellular response to oxidative stress	1	216.1×	0.009	ABCD1
regulation of oxidative phosphorylation	1	200.6×	0.009	ABCD1
cerebral cortex neuron differentiation	1	200.6×	0.009	PEX5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 0 of 6 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
ACRBP	0	0
A2ML1	0	0
ACSM4	0	0
ABCD1	0	0
PEX6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter
PEX6	3.6.4.7	peroxisome-assembly ATPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	2	A2ML1, ABCD1
D	Druggable family + AlphaFold only, no drug	1	PEX6
E	Difficult family or no structure, no drug	3	PEX5, ACRBP, ACSM4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PEX5	0	—
ACRBP	0	—
A2ML1	0	—
ACSM4	0	—
ABCD1	0	—
PEX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.