Cole-Carpenter syndrome 1

Summary

Cole-Carpenter syndrome 1 (MONDO:0007204) is a disease caused by P4HB (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: P4HB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cole-Carpenter syndrome 1
Mondo ID	MONDO:0007204
OMIM	112240
UMLS	C4317154
MedGen	1374755
GARD	0024531
Is cancer (heuristic)	no

Also known as: CLCRP1 · Cole-Carpenter syndrome 1 · Cole-Carpenter syndrome caused by mutation in P4HB · Cole-Carpenter syndrome type 1 · P4HB Cole-Carpenter syndrome

Data availability: 14 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Cole-Carpenter syndrome › Cole-Carpenter syndrome 1

Related subtypes (1): Cole-Carpenter syndrome 2

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

14 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
189337	NM_000918.4(P4HB):c.1178A>G (p.Tyr393Cys)	P4HB	Pathogenic	criteria provided, single submitter
1175197	NM_000918.4(P4HB):c.236dup (p.Leu79fs)	P4HB	Likely pathogenic	criteria provided, single submitter
2053946	NM_000918.4(P4HB):c.1153A>G (p.Lys385Glu)	P4HB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032489	NM_000918.4(P4HB):c.718T>C (p.Phe240Leu)	P4HB	Uncertain significance	criteria provided, single submitter
2412808	NM_000918.4(P4HB):c.1199_1200delinsTT (p.Cys400Phe)	P4HB	Uncertain significance	criteria provided, single submitter
2434539	NM_000918.4(P4HB):c.1453G>C (p.Glu485Gln)	P4HB	Uncertain significance	criteria provided, single submitter
3620879	NM_000918.4(P4HB):c.329C>T (p.Thr110Met)	P4HB	Uncertain significance	criteria provided, multiple submitters, no conflicts
3766801	NM_000918.4(P4HB):c.624+3G>T	P4HB	Uncertain significance	criteria provided, single submitter
3891892	NM_000918.4(P4HB):c.1069A>G (p.Ser357Gly)	P4HB	Uncertain significance	criteria provided, single submitter
931909	NM_000918.4(P4HB):c.1148A>T (p.Asp383Val)	P4HB	Uncertain significance	criteria provided, single submitter
1165301	NM_000918.4(P4HB):c.430G>A (p.Ala144Thr)	P4HB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3766925	NM_000918.4(P4HB):c.84G>A (p.Val28=)	P4HB	Likely benign	criteria provided, single submitter
4685521	NM_000918.4(P4HB):c.764C>T (p.Thr255Ile)	P4HB	Likely benign	criteria provided, single submitter
717520	NM_000918.4(P4HB):c.303C>T (p.Thr101=)	P4HB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
P4HB	Strong	Autosomal dominant	Cole-Carpenter syndrome 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
P4HB	Orphanet:2050	Cole-Carpenter syndrome
P4HB	Orphanet:216796	Osteogenesis imperfecta type 1

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
P4HB	HGNC:8548	ENSG00000185624	P07237	Protein disulfide-isomerase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
P4HB	Protein disulfide-isomerase	This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
P4HB	Enzyme (other)	yes	5.3.4.1	PDI_thioredoxin-like_dom, Prot_disulphide_isomerase, Thioredoxin_domain

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
parotid gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
P4HB	293	ubiquitous	marker	stromal cell of endometrium, parotid gland, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
P4HB	5,111

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
P4HB	P07237	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
VLDL assembly	1	2284.0×	0.003	P4HB
LDL remodeling	1	1903.3×	0.003	P4HB
Interleukin-23 signaling	1	1268.9×	0.003	P4HB
Chylomicron assembly	1	1142.0×	0.003	P4HB
Insulin processing	1	456.8×	0.005	P4HB
Interleukin-12 signaling	1	407.9×	0.005	P4HB
Detoxification of Reactive Oxygen Species	1	300.5×	0.006	P4HB
Hedgehog ligand biogenesis	1	211.5×	0.006	P4HB
Maturation of DENV proteins	1	211.5×	0.006	P4HB
Collagen biosynthesis and modifying enzymes	1	170.4×	0.007	P4HB
Post-translational protein phosphorylation	1	100.2×	0.011	P4HB
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	P4HB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptidyl-proline hydroxylation to 4-hydroxy-L-proline	1	8426.0×	9e-04	P4HB
regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	8426.0×	9e-04	P4HB
interleukin-23-mediated signaling pathway	1	2808.7×	0.002	P4HB
interleukin-12-mediated signaling pathway	1	1872.4×	0.002	P4HB
insulin processing	1	1685.2×	0.002	P4HB
protein folding in endoplasmic reticulum	1	1404.3×	0.002	P4HB
cellular response to interleukin-7	1	1296.3×	0.002	P4HB
positive regulation of viral entry into host cell	1	1203.7×	0.002	P4HB
positive regulation of T cell migration	1	732.7×	0.002	P4HB
positive regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.004	P4HB
positive regulation of cell adhesion	1	271.8×	0.005	P4HB
response to endoplasmic reticulum stress	1	166.8×	0.007	P4HB
endoplasmic reticulum to Golgi vesicle-mediated transport	1	135.9×	0.008	P4HB
cellular response to hypoxia	1	121.2×	0.009	P4HB
protein folding	1	103.4×	0.010	P4HB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
P4HB	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ISOQUERCETIN	2	P4HB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
P4HB	69	Binding:64, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
P4HB	5.3.4.1	protein disulfide-isomerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
ISOQUERCETIN	2	P4HB

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	P4HB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.