Rhizomelic chondrodysplasia punctata type 5

Summary

Rhizomelic chondrodysplasia punctata type 5 (MONDO:0014743) is a disease caused by PEX5 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PEX5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 27
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	rhizomelic chondrodysplasia punctata type 5
Mondo ID	MONDO:0014743
OMIM	616716
Orphanet	468717
DOID	DOID:0110854
UMLS	C4225237
MedGen	900333
GARD	0013320
Is cancer (heuristic)	no

Also known as: PEX5 rhizomelic chondrodysplasia punctata · RCDP5 · Rcdp5 · rhizomelic chondrodysplasia punctata caused by mutation in PEX5 · rhizomelic chondrodysplasia punctata type 5 · rhizomelic chondrodysplasia punctata, type 5

Data availability: 27 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › rhizomelic chondrodysplasia punctata › peroxisome biogenesis disorder due to PEX5 defect in the PEX7-binding domain › rhizomelic chondrodysplasia punctata type 5

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

27 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 6 uncertain significance, 4 pathogenic, 4 pathogenic/likely pathogenic, 3 benign, 2 conflicting classifications of pathogenicity

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
190410	NM_001351132.2(PEX5):c.677dup (p.Val227fs)	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
2978647	NM_001351132.2(PEX5):c.1578T>A (p.Asn526Lys)	PEX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4530662	NM_001351132.2(PEX5):c.653T>C (p.Phe218Ser)	PEX5	Pathogenic	criteria provided, single submitter
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
3068282	NM_001351132.2(PEX5):c.1819dup (p.Leu607fs)	PEX5	Likely pathogenic	criteria provided, single submitter
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
539773	NM_001376.5(DYNC1H1):c.8200G>A (p.Val2734Met)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
768511	NM_001351132.2(PEX5):c.147+77_147+121del	PEX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1361478	NM_001351132.2(PEX5):c.664A>G (p.Ile222Val)	PEX5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1489049	NM_001351132.2(PEX5):c.1870G>A (p.Asp624Asn)	PEX5	Uncertain significance	criteria provided, multiple submitters, no conflicts
194614	NM_001351132.2(PEX5):c.1814G>A (p.Ser605Asn)	PEX5	Uncertain significance	criteria provided, multiple submitters, no conflicts
310418	NM_001351132.2(PEX5):c.533G>A (p.Gly178Glu)	PEX5	Uncertain significance	criteria provided, multiple submitters, no conflicts
310435	NM_001351132.2(PEX5):c.1902G>A (p.Met634Ile)	PEX5	Uncertain significance	criteria provided, multiple submitters, no conflicts
498328	NM_001351132.2(PEX5):c.230G>A (p.Arg77His)	PEX5	Uncertain significance	criteria provided, multiple submitters, no conflicts
235376	NM_001351132.2(PEX5):c.815T>C (p.Met272Thr)	PEX5	Benign	criteria provided, multiple submitters, no conflicts
3390922	NM_001351132.2(PEX5):c.137_147+1del	PEX5	Benign	criteria provided, single submitter
559038	NM_001351132.2(PEX5):c.967-26C>G	PEX5	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 7 · 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	Strong	Autosomal recessive	rhizomelic chondrodysplasia punctata type 5	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
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O

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
PEX5	HGNC:9719	ENSG00000139197	P50542	Peroxisomal targeting signal 1 receptor	gencc,clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	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).
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX5	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, PEX5/PEX5L
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail

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
left testis	1
right testis	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX5	142	ubiquitous	marker	gastrocnemius, left testis, right testis
DYNC1H1	290	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
DYNC1H1	4,215
PEX5	1,741

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
PEX5	P50542	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. 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
Pexophagy	1	475.8×	0.028	PEX5
Aggrephagy	1	124.1×	0.028	DYNC1H1
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.028	DYNC1H1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.028	DYNC1H1
E3 ubiquitin ligases ubiquitinate target proteins	1	96.8×	0.028	PEX5
Peroxisomal protein import	1	86.5×	0.028	PEX5
Loss of Nlp from mitotic centrosomes	1	79.3×	0.028	DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.028	DYNC1H1
AURKA Activation by TPX2	1	76.1×	0.028	DYNC1H1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.028	DYNC1H1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.028	DYNC1H1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.028	DYNC1H1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.028	DYNC1H1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.028	DYNC1H1
COPI-mediated anterograde transport	1	54.9×	0.028	DYNC1H1
EML4 and NUDC in mitotic spindle formation	1	46.4×	0.029	DYNC1H1
MHC class II antigen presentation	1	44.6×	0.029	DYNC1H1
Resolution of Sister Chromatid Cohesion	1	43.3×	0.029	DYNC1H1
HCMV Early Events	1	40.5×	0.029	DYNC1H1
RHO GTPases Activate Formins	1	38.8×	0.029	DYNC1H1
Mitotic Prometaphase	1	34.6×	0.031	DYNC1H1
Separation of Sister Chromatids	1	30.4×	0.034	DYNC1H1
Neutrophil degranulation	1	11.5×	0.085	DYNC1H1

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, docking	1	2106.5×	0.003	PEX5
protein import into peroxisome matrix, translocation	1	2106.5×	0.003	PEX5
protein import into peroxisome matrix, substrate release	1	1685.2×	0.003	PEX5
regulation of metaphase plate congression	1	1685.2×	0.003	DYNC1H1
protein import into peroxisome membrane	1	1404.3×	0.003	PEX5
establishment of spindle localization	1	1404.3×	0.003	DYNC1H1
mitochondrial membrane organization	1	1203.7×	0.003	PEX5
protein import into peroxisome matrix, receptor recycling	1	1203.7×	0.003	PEX5
positive regulation of spindle assembly	1	1053.2×	0.003	DYNC1H1
protein targeting to peroxisome	1	842.6×	0.003	PEX5
positive regulation of intracellular transport	1	842.6×	0.003	DYNC1H1
retrograde axonal transport	1	766.0×	0.003	DYNC1H1
cerebral cortex cell migration	1	766.0×	0.003	PEX5
protein import into peroxisome matrix	1	702.2×	0.003	PEX5
cerebral cortex neuron differentiation	1	601.9×	0.004	PEX5
pexophagy	1	526.6×	0.004	PEX5
P-body assembly	1	526.6×	0.004	DYNC1H1
cell development	1	443.5×	0.004	PEX5
regulation of mitotic spindle organization	1	421.3×	0.004	DYNC1H1
very long-chain fatty acid metabolic process	1	383.0×	0.004	PEX5
nuclear migration	1	366.4×	0.004	DYNC1H1
protein tetramerization	1	312.1×	0.005	PEX5
stress granule assembly	1	300.9×	0.005	DYNC1H1
neuromuscular process	1	263.3×	0.005	PEX5
positive regulation of multicellular organism growth	1	247.8×	0.005	PEX5
negative regulation of protein-containing complex assembly	1	227.7×	0.006	PEX5
endoplasmic reticulum organization	1	210.7×	0.006	PEX5
cellular response to reactive oxygen species	1	205.5×	0.006	PEX5
fatty acid beta-oxidation	1	187.2×	0.006	PEX5
cytoplasmic microtubule organization	1	172.0×	0.007	DYNC1H1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DYNC1H1	1	2
PEX5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DYNC1H1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DYNC1H1	7	Binding:7

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

1 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)
MOLIBRESIB	2	DYNC1H1

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	1	DYNC1H1
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04569162	Not specified	RECRUITING	Rhizomelic Chondrodysplasia Punctata Registry