peroxisome biogenesis disorder 3A (Zellweger)

Summary

peroxisome biogenesis disorder 3A (Zellweger) (MONDO:0013927) is a disease caused by PEX12 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PEX12 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 500

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 3A (Zellweger)
Mondo ID	MONDO:0013927
MeSH	C566633
OMIM	614859
DOID	DOID:0080478
NCIT	C155752
UMLS	C3553929
MedGen	766843
GARD	0015858
Is cancer (heuristic)	no

Also known as: PBD3A · peroxisome biogenesis disorder 3A (Zellweger)

Data availability: 500 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 PEX12 defect › peroxisome biogenesis disorder 3A (Zellweger)

Related subtypes (2): peroxisome biogenesis disorder type 3B, peroxisome biogenesis disorder, complementation group 3

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

500 retrieved; paginated sample, class counts are floors:

200 uncertain significance, 164 likely benign, 59 pathogenic, 32 pathogenic/likely pathogenic, 21 likely pathogenic, 12 conflicting classifications of pathogenicity, 9 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3243102	NC_000017.10:g.(?33445500)(34079869_?)del	AP2B1	Pathogenic	criteria provided, single submitter
1066716	NM_000286.3(PEX12):c.1039_1040del (p.Glu347fs)	PEX12	Pathogenic	criteria provided, single submitter
1069062	NM_000286.3(PEX12):c.920_921del (p.Cys307fs)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069399	NM_000286.3(PEX12):c.969_970del (p.Phe324fs)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069736	NM_000286.3(PEX12):c.910_911del (p.Cys304fs)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069956	NM_000286.3(PEX12):c.174del (p.Trp58fs)	PEX12	Pathogenic	criteria provided, single submitter
1070510	NM_000286.3(PEX12):c.260_261insAA (p.Tyr87Ter)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070935	NM_000286.3(PEX12):c.895A>T (p.Lys299Ter)	PEX12	Pathogenic	criteria provided, single submitter
1075350	NM_000286.3(PEX12):c.331C>T (p.Gln111Ter)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076434	NC_000017.11:g.35577561_35577592del	PEX12	Pathogenic	criteria provided, single submitter
1252073	NM_000286.3(PEX12):c.308dup (p.Leu103fs)	PEX12	Pathogenic	no assertion criteria provided
1367479	NM_000286.3(PEX12):c.795C>G (p.Tyr265Ter)	PEX12	Pathogenic	criteria provided, single submitter
1374439	NM_000286.3(PEX12):c.305_306del (p.Arg102fs)	PEX12	Pathogenic	criteria provided, single submitter
1394011	NM_000286.3(PEX12):c.518G>A (p.Trp173Ter)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1400207	NM_000286.3(PEX12):c.51_54del (p.Gln17fs)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1407609	NM_000286.3(PEX12):c.342G>A (p.Trp114Ter)	PEX12	Pathogenic	criteria provided, single submitter
1416654	NM_000286.3(PEX12):c.151_154del (p.His51fs)	PEX12	Pathogenic	criteria provided, single submitter
1430060	NM_000286.3(PEX12):c.222dup (p.Leu75fs)	PEX12	Pathogenic	criteria provided, single submitter
1435818	NM_000286.3(PEX12):c.471del (p.Ala158fs)	PEX12	Pathogenic	criteria provided, single submitter
1438584	NM_000286.3(PEX12):c.116del (p.His39fs)	PEX12	Pathogenic	criteria provided, single submitter
1439442	NM_000286.3(PEX12):c.126+1G>A	PEX12	Pathogenic	criteria provided, single submitter
1453031	NM_000286.3(PEX12):c.680_680+1delinsCA	PEX12	Pathogenic	criteria provided, single submitter
1454243	NM_000286.3(PEX12):c.842del (p.Thr281fs)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456191	NM_000286.3(PEX12):c.511del (p.Glu171fs)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191074	NM_000286.3(PEX12):c.334C>T (p.Gln112Ter)	PEX12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1939812	NM_000286.3(PEX12):c.348dup (p.Ile117fs)	PEX12	Pathogenic	criteria provided, single submitter
1994220	NM_000286.3(PEX12):c.725del (p.Gly242fs)	PEX12	Pathogenic	criteria provided, single submitter
2000167	NM_000286.3(PEX12):c.669del (p.Gln223fs)	PEX12	Pathogenic	criteria provided, single submitter
2009633	NM_000286.3(PEX12):c.86del (p.Ser28_Leu29insTer)	PEX12	Pathogenic	criteria provided, single submitter
2011680	NM_000286.3(PEX12):c.379A>T (p.Lys127Ter)	PEX12	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
PEX12	Definitive	Autosomal recessive	peroxisome biogenesis disorder	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEX12	Orphanet:44	Neonatal adrenoleukodystrophy
PEX12	Orphanet:772	Infantile Refsum disease
PEX12	Orphanet:912	Zellweger syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PEX12	HGNC:8854	ENSG00000108733	O00623	Peroxisome assembly protein 12	gencc,clinvar
AP2B1	HGNC:563	ENSG00000006125	P63010	AP-2 complex subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEX12	Peroxisome assembly protein 12	Component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling.
AP2B1	AP-2 complex subunit beta	Component of the adaptor protein complex 2 (AP-2).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX12	Transcription factor	no		Pex_N, Znf_RING/FYVE/PHD, PEX12
AP2B1	Antibody/Immunoglobulin	yes		Armadillo, Clathrin/coatomer_adapt-like_N, Clathrin_a/b/g-adaptin_app_Ig

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
choroid plexus epithelium	1
primordial germ cell in gonad	1
secondary oocyte	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX12	270	ubiquitous	yes	secondary oocyte, choroid plexus epithelium, primordial germ cell in gonad
AP2B1	283	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEX12	927
AP2B1	891

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP2B1	P63010	22

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX12	O00623	81.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nef Mediated CD8 Down-regulation	1	815.7×	0.016	AP2B1
Nef Mediated CD4 Down-regulation	1	634.4×	0.016	AP2B1
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	439.2×	0.016	AP2B1
Retrograde neurotrophin signalling	1	407.9×	0.016	AP2B1
WNT5A-dependent internalization of FZD4	1	380.7×	0.016	AP2B1
VLDLR internalisation and degradation	1	356.9×	0.016	AP2B1
Trafficking of GluR2-containing AMPA receptors	1	335.9×	0.016	AP2B1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	317.2×	0.016	AP2B1
The role of Nef in HIV-1 replication and disease pathogenesis	1	317.2×	0.016	AP2B1
LDL clearance	1	271.9×	0.016	AP2B1
Class I peroxisomal membrane protein import	1	259.6×	0.016	PEX12
Plasma lipoprotein clearance	1	237.9×	0.016	AP2B1
Host Interactions of HIV factors	1	167.9×	0.020	AP2B1
PCP/CE pathway	1	150.3×	0.020	AP2B1
Beta-catenin independent WNT signaling	1	146.4×	0.020	AP2B1
Dengue Virus Attachment and Entry	1	129.8×	0.022	AP2B1
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.022	AP2B1
Recycling pathway of L1	1	112.0×	0.022	AP2B1
EPH-ephrin mediated repulsion of cells	1	109.8×	0.022	AP2B1
Signaling by NTRK1 (TRKA)	1	98.5×	0.022	AP2B1
E3 ubiquitin ligases ubiquitinate target proteins	1	96.8×	0.022	PEX12
Signaling by NTRKs	1	90.6×	0.023	AP2B1
Peroxisomal protein import	1	86.5×	0.023	PEX12
EPH-Ephrin signaling	1	82.8×	0.023	AP2B1
L1CAM interactions	1	60.1×	0.029	AP2B1
HIV Infection	1	59.5×	0.029	AP2B1
Potential therapeutics for SARS	1	57.1×	0.029	AP2B1
Signaling by WNT	1	56.0×	0.029	AP2B1
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.029	AP2B1
MHC class II antigen presentation	1	44.6×	0.033	AP2B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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, substrate release	1	1685.2×	0.005	PEX12
protein import into peroxisome matrix, receptor recycling	1	1203.7×	0.005	PEX12
postsynaptic neurotransmitter receptor internalization	1	1053.2×	0.005	AP2B1
protein targeting to peroxisome	1	842.6×	0.005	PEX12
positive regulation of protein localization to membrane	1	842.6×	0.005	AP2B1
protein import into peroxisome matrix	1	702.2×	0.005	PEX12
clathrin coat assembly	1	443.5×	0.006	AP2B1
peroxisome organization	1	401.2×	0.006	PEX12
positive regulation of endocytosis	1	401.2×	0.006	AP2B1
protein quality control for misfolded or incompletely synthesized proteins	1	383.0×	0.006	PEX12
neurotransmitter secretion	1	351.1×	0.006	AP2B1
coronary vasculature development	1	312.1×	0.006	AP2B1
clathrin-dependent endocytosis	1	290.6×	0.006	AP2B1
aorta development	1	280.9×	0.006	AP2B1
ventricular septum development	1	247.8×	0.006	AP2B1
synaptic vesicle endocytosis	1	216.1×	0.007	AP2B1
cellular response to reactive oxygen species	1	205.5×	0.007	PEX12
protein monoubiquitination	1	172.0×	0.007	PEX12
kidney development	1	70.2×	0.017	AP2B1
protein polyubiquitination	1	57.7×	0.020	PEX12
vesicle-mediated transport	1	48.1×	0.023	AP2B1
intracellular protein transport	1	32.4×	0.032	AP2B1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.038	PEX12

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PEX12	0	0
AP2B1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AP2B1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	AP2B1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PEX12

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PEX12	0	—
AP2B1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.