peroxisome biogenesis disorder 8A (Zellweger)

Summary

peroxisome biogenesis disorder 8A (Zellweger) (MONDO:0013942) is a disease caused by PEX16 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PEX16 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 56

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 8A (Zellweger)
Mondo ID	MONDO:0013942
OMIM	614876
DOID	DOID:0080483
UMLS	C3553959
MedGen	766873
GARD	0015869
Is cancer (heuristic)	no

Also known as: PBD8A · peroxisome biogenesis disorder 8A (Zellweger)

Data availability: 56 ClinVar variants · 2 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 PEX16 defect › peroxisome biogenesis disorder 8A (Zellweger)

Related subtypes (1): peroxisome biogenesis disorder 8B

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

56 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 15 conflicting classifications of pathogenicity, 7 benign, 6 benign/likely benign, 2 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
561075	NM_004813.4(PEX16):c.859C>T (p.Arg287Cys)	PEX16	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6466	NM_004813.4(PEX16):c.526C>T (p.Arg176Ter)	PEX16	Pathogenic	criteria provided, multiple submitters, no conflicts
6467	NM_004813.4(PEX16):c.952+2T>C	PEX16	Pathogenic	no assertion criteria provided
3599610	NM_004813.4(PEX16):c.638del (p.Leu213fs)	PEX16	Likely pathogenic	criteria provided, single submitter
909634	NM_000255.4(MMUT):c.1963C>T (p.Arg655Cys)	MMUT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339506	NM_004813.4(PEX16):c.460+5G>A	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196397	NM_004813.4(PEX16):c.204G>T (p.Glu68Asp)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198814	NM_004813.4(PEX16):c.695-6C>T	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286888	NM_004813.4(PEX16):c.1002T>C (p.Ser334=)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304789	NM_004813.4(PEX16):c.726G>A (p.Ser242=)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304790	NM_004813.4(PEX16):c.699C>T (p.Leu233=)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304791	NM_004813.4(PEX16):c.694+11C>T	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304793	NM_004813.4(PEX16):c.609C>T (p.His203=)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304795	NM_004813.4(PEX16):c.360-7G>A	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304796	NM_004813.4(PEX16):c.348C>T (p.Val116=)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498836	NM_004813.4(PEX16):c.262G>A (p.Val88Met)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878684	NM_004813.4(PEX16):c.672C>T (p.Tyr224=)	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880426	NM_004813.4(PEX16):c.*70C>G	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880471	NM_004813.4(PEX16):c.149-13C>G	PEX16	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032942	NM_004813.4(PEX16):c.227C>T (p.Ser76Leu)	PEX16	Uncertain significance	criteria provided, multiple submitters, no conflicts
282806	NM_004813.4(PEX16):c.877C>T (p.Arg293Cys)	PEX16	Uncertain significance	criteria provided, multiple submitters, no conflicts
304773	NM_004813.4(PEX16):c.*557G>C	PEX16	Uncertain significance	criteria provided, single submitter
304774	NM_004813.4(PEX16):c.*491G>A	PEX16	Uncertain significance	criteria provided, single submitter
304777	NM_004813.4(PEX16):c.*376G>A	PEX16	Uncertain significance	criteria provided, single submitter
304779	NM_004813.4(PEX16):c.*324G>A	PEX16	Uncertain significance	criteria provided, single submitter
304780	NM_004813.4(PEX16):c.*309G>C	PEX16	Uncertain significance	criteria provided, single submitter
304782	NM_004813.4(PEX16):c.*277C>T	PEX16	Uncertain significance	criteria provided, single submitter
304784	NM_004813.4(PEX16):c.*107C>T	PEX16	Uncertain significance	criteria provided, single submitter
304786	NM_004813.4(PEX16):c.946G>A (p.Val316Ile)	PEX16	Uncertain significance	criteria provided, multiple submitters, no conflicts
304787	NM_004813.4(PEX16):c.918G>C (p.Leu306=)	PEX16	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PEX16	Definitive	Autosomal recessive	peroxisome biogenesis disorder 8A (Zellweger)	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEX16	Orphanet:44	Neonatal adrenoleukodystrophy
PEX16	Orphanet:642954	Autosomal recessive ataxia due to PEX16 deficiency
PEX16	Orphanet:772	Infantile Refsum disease
PEX16	Orphanet:912	Zellweger syndrome
MMUT	Orphanet:289916	Vitamin B12-unresponsive methylmalonic acidemia type mut0
MMUT	Orphanet:79312	Vitamin B12-unresponsive methylmalonic acidemia type mut-

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
PEX16	HGNC:8857	ENSG00000121680	Q9Y5Y5	Peroxisomal membrane protein PEX16	gencc,clinvar
MMUT	HGNC:7526	ENSG00000146085	P22033	Methylmalonyl-CoA mutase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEX16	Peroxisomal membrane protein PEX16	Required for peroxisome membrane biogenesis.
MMUT	Methylmalonyl-CoA mutase, mitochondrial	Catalyzes the reversible isomerization of methylmalonyl-CoA (MMCoA) (generated from branched-chain amino acid metabolism and degradation of dietary odd chain fatty acids and cholesterol) to succinyl-CoA (3-carboxypropionyl-CoA), a key inte…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX16	Other/Unknown	no		Pex16
MMUT	Enzyme (other)	yes	5.4.99.2	MMCoA_mutase_a_cat, MeMalonylCoA_mutase_a/b_cat, Cobalamin-bd

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
granulocyte	1
prefrontal cortex	1
right lobe of liver	1
choroid plexus epithelium	1
nephron tubule	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX16	281	ubiquitous	marker	prefrontal cortex, granulocyte, right lobe of liver
MMUT	296	ubiquitous	marker	choroid plexus epithelium, oocyte, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMUT	3,709
PEX16	1,231

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMUT	P22033	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX16	Q9Y5Y5	83.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Defective MMAA causes MMA, cblA type	1	2855.0×	0.002	MMUT
Defective MUT causes MMAM	1	2855.0×	0.002	MMUT
Diseases of mitochondrial beta oxidation	1	2855.0×	0.002	MMUT
Diseases of propionyl-CoA catabolism	1	2855.0×	0.002	MMUT
Propionyl-CoA catabolism	1	1142.0×	0.003	MMUT
Cobalamin (Cbl) metabolism	1	634.4×	0.005	MMUT
Defects in cobalamin (B12) metabolism	1	407.9×	0.006	MMUT
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.007	MMUT
Defects in vitamin and cofactor metabolism	1	300.5×	0.007	MMUT
Class I peroxisomal membrane protein import	1	259.6×	0.007	PEX16
Mitochondrial Fatty Acid Beta-Oxidation	1	190.3×	0.009	MMUT
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.017	MMUT
Fatty acid metabolism	1	65.6×	0.021	MMUT
Metabolism of vitamins and cofactors	1	58.3×	0.022	MMUT
Diseases of metabolism	1	40.2×	0.030	MMUT
Metabolism of lipids	1	15.8×	0.070	MMUT
Disease	1	6.5×	0.156	MMUT
Metabolism	1	5.8×	0.165	MMUT

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
obsolete propionate metabolic process, methylmalonyl pathway	1	8426.0×	5e-04	MMUT
ER-dependent peroxisome organization	1	8426.0×	5e-04	PEX16
ER-dependent peroxisome localization	1	8426.0×	5e-04	PEX16
succinyl-CoA biosynthetic process	1	4213.0×	8e-04	MMUT
peroxisome membrane biogenesis	1	2808.7×	9e-04	PEX16
protein to membrane docking	1	1685.2×	0.001	PEX16
protein import into peroxisome membrane	1	1404.3×	0.001	PEX16
homocysteine metabolic process	1	936.2×	0.002	MMUT
protein targeting to peroxisome	1	842.6×	0.002	PEX16
protein import into peroxisome matrix	1	702.2×	0.002	PEX16
peroxisome organization	1	401.2×	0.003	PEX16
positive regulation of GTPase activity	1	138.1×	0.008	MMUT
post-embryonic development	1	102.8×	0.010	MMUT

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
PEX16	0	0
MMUT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PEX16	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMUT	5.4.99.2	methylmalonyl-CoA mutase

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	MMUT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PEX16

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)
PEX16	1	—
MMUT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.