MEGF8-related Carpenter syndrome

Summary

MEGF8-related Carpenter syndrome (MONDO:0013998) is a disease caused by MEGF8 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: MEGF8 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 698

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	MEGF8-related Carpenter syndrome
Mondo ID	MONDO:0013998
OMIM	614976
DOID	DOID:0061099
UMLS	C3554247
MedGen	767161
GARD	0015889
Is cancer (heuristic)	no

Also known as: Carpenter syndrome 2 · Carpenter syndrome caused by mutation in MEGF8 · Carpenter syndrome type 2 · CRPT2 · MEGF8 Carpenter syndrome

Data availability: 698 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › acrocephalosyndactyly › acrocephalopolysyndactyly › Carpenter syndrome › MEGF8-related Carpenter syndrome

Related subtypes (1): RAB23-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

600 retrieved; paginated sample, class counts are floors:

279 likely benign, 213 uncertain significance, 36 benign, 21 pathogenic, 19 benign/likely benign, 15 conflicting classifications of pathogenicity, 14 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1162320	NM_001271938.2(MEGF8):c.5073del (p.Phe1692fs)	MEGF8	Pathogenic	no assertion criteria provided
1450222	NM_001271938.2(MEGF8):c.1255C>T (p.Arg419Ter)	MEGF8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2037327	NM_001271938.2(MEGF8):c.4451_4452delinsGCA (p.Leu1484fs)	MEGF8	Pathogenic	criteria provided, single submitter
2081222	NM_001271938.2(MEGF8):c.3577C>T (p.Arg1193Ter)	MEGF8	Pathogenic	criteria provided, single submitter
2128019	NM_001271938.2(MEGF8):c.3441del (p.Thr1149fs)	MEGF8	Pathogenic	criteria provided, single submitter
2726282	NM_001271938.2(MEGF8):c.6301C>T (p.Arg2101Ter)	MEGF8	Pathogenic	criteria provided, single submitter
2988042	NM_001271938.2(MEGF8):c.2971C>T (p.Arg991Ter)	MEGF8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3067104	NM_001271938.2(MEGF8):c.2499+1G>A	MEGF8	Pathogenic	no assertion criteria provided
3067105	NM_001271938.2(MEGF8):c.5844+1G>A	MEGF8	Pathogenic	no assertion criteria provided
3067111	NM_001271938.2(MEGF8):c.7992_7995del (p.Leu2665fs)	MEGF8	Pathogenic	no assertion criteria provided
3673024	NM_001271938.2(MEGF8):c.4227del (p.Gly1411fs)	MEGF8	Pathogenic	criteria provided, single submitter
39845	NM_001271938.2(MEGF8):c.4697G>A (p.Arg1566His)	MEGF8	Pathogenic/Likely pathogenic	no assertion criteria provided
39846	NM_001271938.2(MEGF8):c.7300A>G (p.Ser2434Gly)	MEGF8	Pathogenic	no assertion criteria provided
39847	NM_001271938.2(MEGF8):c.1342C>T (p.Arg448Ter)	MEGF8	Pathogenic	no assertion criteria provided
39848	NM_001271938.2(MEGF8):c.595G>C (p.Gly199Arg)	MEGF8	Pathogenic	no assertion criteria provided
4294361	NM_001271938.2(MEGF8):c.634del (p.Ala212fs)	MEGF8	Pathogenic	criteria provided, single submitter
4706279	NM_001271938.2(MEGF8):c.4108C>T (p.Arg1370Ter)	MEGF8	Pathogenic	criteria provided, single submitter
4720696	NM_001271938.2(MEGF8):c.116_125del (p.Glu39fs)	MEGF8	Pathogenic	criteria provided, single submitter
4723779	NM_001271938.2(MEGF8):c.2086C>T (p.Gln696Ter)	MEGF8	Pathogenic	criteria provided, single submitter
4743508	NM_001271938.2(MEGF8):c.5253dup (p.Phe1752fs)	MEGF8	Pathogenic	criteria provided, single submitter
4751010	NM_001271938.2(MEGF8):c.4885C>T (p.Arg1629Ter)	MEGF8	Pathogenic	criteria provided, single submitter
4768373	NM_001271938.2(MEGF8):c.283C>T (p.Arg95Ter)	MEGF8	Pathogenic	criteria provided, single submitter
561058	NM_001271938.2(MEGF8):c.1788+1G>C	MEGF8	Pathogenic	criteria provided, single submitter
584047	NC_000019.10:g.(?42370701)(42370831_?)del	MEGF8	Pathogenic	criteria provided, single submitter
1164007	NM_001271938.2(MEGF8):c.7970_7972del (p.Ser2657del)	MEGF8	Likely pathogenic	criteria provided, single submitter
1703133	NM_001271938.2(MEGF8):c.3931G>T (p.Glu1311Ter)	MEGF8	Likely pathogenic	criteria provided, single submitter
1915186	NM_001271938.2(MEGF8):c.3761+2T>C	MEGF8	Likely pathogenic	criteria provided, single submitter
2017970	NM_001271938.2(MEGF8):c.1784_1788+3del	MEGF8	Likely pathogenic	criteria provided, single submitter
3067103	NM_001271938.2(MEGF8):c.878T>C (p.Leu293Pro)	MEGF8	Likely pathogenic	no assertion criteria provided
3067109	NM_001271938.2(MEGF8):c.7961TCT[2] (p.Phe2656del)	MEGF8	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
MEGF8	HGNC:3233	ENSG00000105429	Q7Z7M0	Multiple epidermal growth factor-like domains protein 8	gencc,clinvar
ACTMAP	HGNC:24758	ENSG00000188493	Q5BKX5	Actin maturation protease	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MEGF8	Multiple epidermal growth factor-like domains protein 8	Acts as a negative regulator of hedgehog signaling.
ACTMAP	Actin maturation protease	Actin maturation protease that specifically mediates the cleavage of immature acetylated N-terminal actin, thereby contributing to actin maturation.

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)
MEGF8	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
ACTMAP	Other/Unknown	no		ACTMAP

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
cortical plate	1
middle temporal gyrus	1
prefrontal cortex	1
hindlimb stylopod muscle	1
pancreatic ductal cell	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MEGF8	258	ubiquitous	yes	cortical plate, middle temporal gyrus, prefrontal cortex
ACTMAP	266	ubiquitous	marker	pancreatic ductal cell, primordial germ cell in gonad, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTMAP	1,011
MEGF8	1,007

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MEGF8	Q7Z7M0	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTMAP	Q5BKX5	83.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
epiboly involved in gastrulation with mouth forming second	1	8426.0×	0.003	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×	0.003	MEGF8
pharyngeal arch artery morphogenesis	1	842.6×	0.003	MEGF8
craniofacial suture morphogenesis	1	842.6×	0.003	MEGF8
cell migration involved in gastrulation	1	766.0×	0.003	MEGF8
limb morphogenesis	1	526.6×	0.004	MEGF8
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×	0.007	MEGF8
embryonic skeletal system morphogenesis	1	195.9×	0.007	MEGF8
embryonic digit morphogenesis	1	150.5×	0.009	MEGF8
BMP signaling pathway	1	100.3×	0.012	MEGF8
smoothened signaling pathway	1	90.6×	0.013	MEGF8
protein processing	1	85.1×	0.013	ACTMAP
protein-containing complex assembly	1	56.9×	0.019	MEGF8
regulation of gene expression	1	41.7×	0.025	MEGF8
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
MEGF8	0	0
ACTMAP	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	MEGF8, ACTMAP

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)
MEGF8	0	—
ACTMAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.