peroxisome biogenesis disorder 12A (Zellweger)

Summary

peroxisome biogenesis disorder 12A (Zellweger) (MONDO:0013951) is a disease caused by PEX19 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PEX19 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 412

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 12A (Zellweger)
Mondo ID	MONDO:0013951
OMIM	614886
DOID	DOID:0080486
UMLS	C3554002
MedGen	766916
GARD	0015876
Is cancer (heuristic)	no

Also known as: PBD12A · peroxisome biogenesis disorder 12A (Zellweger)

Data availability: 412 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 PEX19 defect › peroxisome biogenesis disorder 12A (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

412 retrieved; paginated sample, class counts are floors:

196 uncertain significance, 152 likely benign, 25 conflicting classifications of pathogenicity, 12 benign, 10 pathogenic, 9 likely pathogenic, 7 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1385253	NM_002857.4(PEX19):c.294del (p.Glu98fs)	PEX19	Pathogenic	criteria provided, single submitter
1444009	NM_002857.4(PEX19):c.398dup (p.Ser134fs)	PEX19	Pathogenic	criteria provided, single submitter
1521989	NM_002857.4(PEX19):c.161C>T (p.Ser54Leu)	PEX19	Pathogenic	criteria provided, multiple submitters, no conflicts
2011554	NM_002857.4(PEX19):c.9del (p.Ala4fs)	PEX19	Pathogenic	criteria provided, single submitter
2088255	NM_002857.4(PEX19):c.526C>T (p.Gln176Ter)	PEX19	Pathogenic	criteria provided, single submitter
2842183	NM_002857.4(PEX19):c.86del (p.Phe29fs)	PEX19	Pathogenic	criteria provided, single submitter
2858439	NM_002857.4(PEX19):c.577A>T (p.Lys193Ter)	PEX19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30062	NM_002857.4(PEX19):c.320del (p.Lys107fs)	PEX19	Pathogenic	no assertion criteria provided
3680741	NM_002857.4(PEX19):c.262del (p.Glu88fs)	PEX19	Pathogenic	criteria provided, single submitter
4715460	NM_002857.4(PEX19):c.326C>G (p.Ser109Ter)	PEX19	Pathogenic	criteria provided, single submitter
4774519	NM_002857.4(PEX19):c.430C>T (p.Gln144Ter)	PEX19	Pathogenic	criteria provided, single submitter
1066259	NM_002857.4(PEX19):c.346+2T>C	PEX19	Likely pathogenic	criteria provided, single submitter
1066362	NM_002857.4(PEX19):c.181-2A>G	PEX19	Likely pathogenic	criteria provided, single submitter
1067988	NM_002857.4(PEX19):c.346+1G>A	PEX19	Likely pathogenic	criteria provided, single submitter
1324882	NM_002857.4(PEX19):c.180+1G>T	PEX19	Likely pathogenic	criteria provided, single submitter
2122971	NM_002857.4(PEX19):c.70+2T>G	PEX19	Likely pathogenic	criteria provided, single submitter
2432567	NM_002857.4(PEX19):c.281T>A (p.Leu94Ter)	PEX19	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2806573	NM_002857.4(PEX19):c.594+1G>C	PEX19	Likely pathogenic	criteria provided, single submitter
3599001	NM_002857.4(PEX19):c.397_400del (p.Leu133fs)	PEX19	Likely pathogenic	criteria provided, single submitter
3659074	NM_002857.4(PEX19):c.181-1G>A	PEX19	Likely pathogenic	criteria provided, single submitter
281660	NM_002857.4(PEX19):c.181-5C>T	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284050	NM_002857.4(PEX19):c.261C>T (p.Phe87=)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286120	NM_002857.4(PEX19):c.195T>C (p.Ala65=)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287774	NM_002857.4(PEX19):c.16G>A (p.Glu6Lys)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288371	NM_002857.4(PEX19):c.255G>A (p.Ala85=)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291028	NM_002857.4(PEX19):c.21C>G (p.Gly7=)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291104	NM_002857.4(PEX19):c.162G>T (p.Ser54=)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293227	NM_002857.4(PEX19):c.498T>G (p.Asp166Glu)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293228	NM_002857.4(PEX19):c.459G>A (p.Leu153=)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293230	NM_002857.4(PEX19):c.402T>C (p.Ser134=)	PEX19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
PEX19	Definitive	Autosomal recessive	peroxisome biogenesis disorder 12A (Zellweger)	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEX19	Orphanet:44	Neonatal adrenoleukodystrophy
PEX19	Orphanet:772	Infantile Refsum disease
PEX19	Orphanet:912	Zellweger syndrome
ATP1A2	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A2	Orphanet:569	Familial or sporadic hemiplegic migraine

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
PEX19	HGNC:9713	ENSG00000162735	P40855	Peroxisomal biogenesis factor 19	gencc,clinvar
ATP1A2	HGNC:800	ENSG00000018625	P50993	Sodium/potassium-transporting ATPase subunit alpha-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEX19	Peroxisomal biogenesis factor 19	Necessary for early peroxisomal biogenesis.
ATP1A2	Sodium/potassium-transporting ATPase subunit alpha-2	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX19	Other/Unknown	no		Pex19, Pex19_C_sf
ATP1A2	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
lateral globus pallidus	1
superior vestibular nucleus	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX19	282	ubiquitous	marker	hindlimb stylopod muscle, muscle of leg, gastrocnemius
ATP1A2	262	broad	marker	lateral globus pallidus, trigeminal ganglion, superior vestibular nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A2	2,679
PEX19	2,544

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PEX19	P40855	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP1A2	P50993	88.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
ABC transporters in lipid homeostasis	1	300.5×	0.027	PEX19
Class I peroxisomal membrane protein import	1	259.6×	0.027	PEX19
Ion transport by P-type ATPases	1	103.8×	0.034	ATP1A2
Ion homeostasis	1	102.0×	0.034	ATP1A2
Potential therapeutics for SARS	1	57.1×	0.041	ATP1A2
Cardiac conduction	1	54.4×	0.041	ATP1A2
Ion channel transport	1	48.0×	0.041	ATP1A2
Muscle contraction	1	38.6×	0.045	ATP1A2
SARS-CoV Infections	1	27.7×	0.056	ATP1A2
Dengue Virus-Host Interactions	1	22.8×	0.061	PEX19
Viral Infection Pathways	1	15.4×	0.081	ATP1A2
Transport of small molecules	1	12.6×	0.085	ATP1A2
Infectious disease	1	12.4×	0.085	ATP1A2
Disease	1	6.5×	0.147	ATP1A2

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
olfactory cortex development	1	8426.0×	0.002	ATP1A2
establishment of protein localization to peroxisome	1	8426.0×	0.002	PEX19
negative regulation of lipid binding	1	8426.0×	0.002	PEX19
regulation of glutamate uptake involved in transmission of nerve impulse	1	4213.0×	0.003	ATP1A2
negative regulation of calcium ion transmembrane transport	1	4213.0×	0.003	ATP1A2
peroxisome membrane biogenesis	1	2808.7×	0.003	PEX19
negative regulation of striated muscle contraction	1	2808.7×	0.003	ATP1A2
negative regulation of heart contraction	1	2106.5×	0.003	ATP1A2
amygdala development	1	1404.3×	0.003	ATP1A2
protein import into peroxisome membrane	1	1404.3×	0.003	PEX19
response to glycoside	1	1203.7×	0.003	ATP1A2
regulation of striated muscle contraction	1	1053.2×	0.003	ATP1A2
response to potassium ion	1	1053.2×	0.003	ATP1A2
positive regulation of heart contraction	1	1053.2×	0.003	ATP1A2
protein targeting to peroxisome	1	842.6×	0.003	PEX19
regulation of muscle contraction	1	842.6×	0.003	ATP1A2
peroxisome fission	1	766.0×	0.003	PEX19
L-ascorbic acid metabolic process	1	766.0×	0.003	ATP1A2
locomotion	1	766.0×	0.003	ATP1A2
neurotransmitter uptake	1	702.2×	0.003	ATP1A2
neuronal action potential propagation	1	702.2×	0.003	ATP1A2
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.003	ATP1A2
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.003	ATP1A2
regulation of respiratory gaseous exchange by nervous system process	1	648.1×	0.003	ATP1A2
negative regulation of cytosolic calcium ion concentration	1	648.1×	0.003	ATP1A2
relaxation of cardiac muscle	1	648.1×	0.003	ATP1A2
membrane repolarization	1	648.1×	0.003	ATP1A2
regulation of smooth muscle contraction	1	601.9×	0.003	ATP1A2
regulation of cardiac muscle cell contraction	1	561.7×	0.003	ATP1A2
sodium ion export across plasma membrane	1	526.6×	0.003	ATP1A2

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATP1A2	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP1A2	5	4
PEX19	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	ATP1A2
DIGOXIN	4	ATP1A2
DIGITOXIN	4	ATP1A2
LANSOPRAZOLE	4	ATP1A2
ROSTAFUROXIN	2	ATP1A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATP1A2	49	Binding:49

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

5 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.

Compound	Max phase	Cohort target (bioactivity)
OMEPRAZOLE	4	ATP1A2
DIGOXIN	4	ATP1A2
DIGITOXIN	4	ATP1A2
LANSOPRAZOLE	4	ATP1A2
ROSTAFUROXIN	2	ATP1A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP1A2
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	PEX19

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)
PEX19	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.