Carpenter syndrome

Summary

Carpenter syndrome (MONDO:0019012) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 184
• Phenotypes (HPO): 40

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		70	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0001156	Brachydactyly	Obligate (100%)
HP:0001770	Toe syndactyly	Obligate (100%)
HP:0006101	Finger syndactyly	Obligate (100%)
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000098	Tall stature	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000263	Oxycephaly	Very frequent (80-99%)
HP:0000275	Narrow face	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000929	Abnormal skull morphology	Very frequent (80-99%)
HP:0001159	Syndactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001357	Plagiocephaly	Very frequent (80-99%)
HP:0001363	Craniosynostosis	Very frequent (80-99%)
HP:0001513	Obesity	Very frequent (80-99%)
HP:0003241	External genital hypoplasia	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0005487	Prominent metopic ridge	Very frequent (80-99%)
HP:0010442	Polydactyly	Very frequent (80-99%)
HP:0000262	Turricephaly	Frequent (30-79%)
HP:0000445	Wide nose	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000481	Abnormal cornea morphology	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0001162	Postaxial hand polydactyly	Frequent (30-79%)
HP:0001841	Preaxial foot polydactyly	Frequent (30-79%)
HP:0002676	Cloverleaf skull	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0011304	Broad thumb	Frequent (30-79%)
HP:0012243	Abnormal reproductive system morphology	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001748	Polysplenia	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0010044	Short 4th metacarpal	Occasional (5-29%)
HP:0100490	Camptodactyly of finger	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Carpenter syndrome
Mondo ID	MONDO:0019012
OMIM	201000
Orphanet	65759
DOID	DOID:0060234
ICD-11	2132713612
NCIT	C98873
SNOMED CT	403767009
UMLS	C1275078
MedGen	226897
GARD	0006003
NORD	897
Is cancer (heuristic)	no

Also known as: ACPS2 · acrocephalopolysyndactyly type 2 · acrocephalopolysyndactyly type II · acrocephalosyndactyly, type II · Carpenter ’s syndrome · Carpenter syndrome · type II Acrocephalopolysyndactyly

Data availability: 184 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › acrocephalosyndactyly › acrocephalopolysyndactyly › Carpenter syndrome

Related subtypes (3): Sakati-Nyhan syndrome, Pfeiffer syndrome, Goodman syndrome

Subtypes (2): RAB23-related Carpenter syndrome, MEGF8-related Carpenter syndrome

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

184 retrieved; paginated sample, class counts are floors:

128 likely benign, 15 pathogenic, 12 uncertain significance, 10 likely pathogenic, 9 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 3 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070344	NM_016277.5(RAB23):c.82del (p.Arg28fs)	RAB23	Pathogenic	criteria provided, single submitter
1071136	NM_016277.5(RAB23):c.421A>T (p.Lys141Ter)	RAB23	Pathogenic	criteria provided, single submitter
1073623	NM_016277.5(RAB23):c.145C>T (p.Arg49Ter)	RAB23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1366841	NM_016277.5(RAB23):c.526C>T (p.Gln176Ter)	RAB23	Pathogenic	criteria provided, single submitter
2017670	NM_016277.5(RAB23):c.426del (p.Arg142fs)	RAB23	Pathogenic	criteria provided, single submitter
2691650	NM_016277.5(RAB23):c.467del (p.Leu156fs)	RAB23	Pathogenic	criteria provided, single submitter
2740005	NM_016277.5(RAB23):c.238C>T (p.Arg80Ter)	RAB23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280858	NM_016277.5(RAB23):c.82C>T (p.Arg28Ter)	RAB23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2827988	NM_016277.5(RAB23):c.430_431del (p.Lys144fs)	RAB23	Pathogenic	criteria provided, single submitter
3008390	NM_016277.5(RAB23):c.313_316del (p.Glu105fs)	RAB23	Pathogenic	criteria provided, single submitter
3245987	NC_000006.11:g.(?57075004)(57075178_?)del	RAB23	Pathogenic	criteria provided, single submitter
3245988	NC_000006.11:g.(?57061071)(57061424_?)del	RAB23	Pathogenic	criteria provided, single submitter
417740	NM_016277.5(RAB23):c.481G>C (p.Val161Leu)	RAB23	Pathogenic	no assertion criteria provided
4591	NM_016277.5(RAB23):c.434T>A (p.Leu145Ter)	RAB23	Pathogenic	criteria provided, multiple submitters, no conflicts
4592	NM_016277.5(RAB23):c.408dup (p.Glu137Ter)	RAB23	Pathogenic	criteria provided, multiple submitters, no conflicts
664887	NM_016277.5(RAB23):c.5del (p.Leu2fs)	RAB23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
832125	NC_000006.12:g.(?57186982)(57222324_?)del	RAB23	Pathogenic	criteria provided, single submitter
954806	NM_016277.5(RAB23):c.17del (p.Met6fs)	RAB23	Pathogenic	criteria provided, single submitter
963114	NM_016277.5(RAB23):c.142G>T (p.Glu48Ter)	RAB23	Pathogenic	criteria provided, single submitter
1217298	NM_001271938.2(MEGF8):c.7005+1G>T	MEGF8	Likely pathogenic	criteria provided, single submitter
1804730	NM_001271938.2(MEGF8):c.7024G>T (p.Glu2342Ter)	MEGF8	Likely pathogenic	criteria provided, single submitter
2501122	NC_000019.9:g.(42830583_42837756)_(42838366_42839186)del	MEGF8	Likely pathogenic	criteria provided, single submitter
2501123	NM_001271938.2(MEGF8):c.1741C>T (p.Gln581Ter)	MEGF8	Likely pathogenic	criteria provided, single submitter
1347492	NM_016277.5(RAB23):c.156-1G>C	RAB23	Likely pathogenic	criteria provided, single submitter
1476916	NM_016277.5(RAB23):c.358_398+177delinsGGTGTACAGTTG	RAB23	Likely pathogenic	criteria provided, single submitter
1498654	NM_016277.5(RAB23):c.482-1_486del	RAB23	Likely pathogenic	criteria provided, single submitter
2120775	NM_016277.5(RAB23):c.481+1G>A	RAB23	Likely pathogenic	criteria provided, single submitter
2813651	NM_016277.5(RAB23):c.174_241+587delinsTTATCATTAA	RAB23	Likely pathogenic	criteria provided, single submitter
3384105	NM_016277.5(RAB23):c.482-1G>A	RAB23	Likely pathogenic	criteria provided, single submitter
1055018	NM_016277.5(RAB23):c.712T>G (p.Ter238Glu)	RAB23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
MEGF8	Definitive	Autosomal recessive	MEGF8-related Carpenter syndrome	6
RAB23	Definitive	Autosomal recessive	RAB23-related Carpenter syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB23	Orphanet:65759	Carpenter syndrome
MEGF8	Orphanet:65759	Carpenter 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
RAB23	HGNC:14263	ENSG00000112210	Q9ULC3	Ras-related protein Rab-23	gencc,clinvar
MEGF8	HGNC:3233	ENSG00000105429	Q7Z7M0	Multiple epidermal growth factor-like domains protein 8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB23	Ras-related protein Rab-23	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
MEGF8	Multiple epidermal growth factor-like domains protein 8	Acts as a negative regulator of hedgehog signaling.

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)
RAB23	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
MEGF8	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom

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
cauda epididymis	1
saphenous vein	1
secondary oocyte	1
cortical plate	1
middle temporal gyrus	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB23	264	ubiquitous	marker	cauda epididymis, saphenous vein, secondary oocyte
MEGF8	258	ubiquitous	yes	cortical plate, middle temporal gyrus, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAB23	1,223
MEGF8	1,007

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAB23	Q9ULC3	6
MEGF8	Q7Z7M0	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
RAB geranylgeranylation	1	173.0×	0.006	RAB23

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
craniofacial suture morphogenesis	2	1685.2×	1e-05	RAB23, MEGF8
epiboly involved in gastrulation with mouth forming second	1	8426.0×	0.002	MEGF8
fasciculation of sensory neuron axon	1	2808.7×	0.003	MEGF8
left/right pattern formation	1	1685.2×	0.003	MEGF8
determination of heart left/right asymmetry	1	1685.2×	0.003	MEGF8
embryonic heart tube left/right pattern formation	1	1404.3×	0.003	MEGF8
determination of digestive tract left/right asymmetry	1	1404.3×	0.003	MEGF8
positive regulation of axon extension involved in axon guidance	1	1203.7×	0.003	MEGF8
embryonic heart tube morphogenesis	1	936.2×	0.004	MEGF8
pharyngeal arch artery morphogenesis	1	842.6×	0.004	MEGF8
cell migration involved in gastrulation	1	766.0×	0.004	MEGF8
GTP metabolic process	1	561.7×	0.004	RAB23
limb morphogenesis	1	526.6×	0.004	MEGF8
negative regulation of protein import into nucleus	1	468.1×	0.005	RAB23
embryonic brain development	1	401.2×	0.005	MEGF8
coronary vasculature development	1	312.1×	0.006	MEGF8
aorta development	1	280.9×	0.006	MEGF8
negative regulation of smoothened signaling pathway	1	227.7×	0.007	MEGF8
embryonic limb morphogenesis	1	200.6×	0.008	MEGF8
embryonic skeletal system morphogenesis	1	195.9×	0.008	MEGF8
cellular defense response	1	159.0×	0.009	RAB23
embryonic digit morphogenesis	1	150.5×	0.009	MEGF8
autophagosome assembly	1	112.3×	0.012	RAB23
BMP signaling pathway	1	100.3×	0.012	MEGF8
smoothened signaling pathway	1	90.6×	0.013	MEGF8
protein-containing complex assembly	1	56.9×	0.020	MEGF8
regulation of gene expression	1	41.7×	0.026	MEGF8
cilium assembly	1	36.8×	0.029	RAB23
intracellular protein transport	1	32.4×	0.032	RAB23
protein ubiquitination	1	20.7×	0.048	MEGF8

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAB23	0	0
MEGF8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RAB23, MEGF8

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)
RAB23	0	—
MEGF8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.