3MC syndrome 1

Summary

3MC syndrome 1 (MONDO:0009770) is a disease caused by MASP1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MASP1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 132

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	3MC syndrome 1
Mondo ID	MONDO:0009770
EFO	EFO:1001978
OMIM	257920
Orphanet	2506
DOID	DOID:0060575
UMLS	C0796059
MedGen	167100
GARD	0004049
Is cancer (heuristic)	no

Also known as: 3MC syndrome 1 · 3MC syndrome caused by mutation in MASP1 · 3MC syndrome type 1 · 3Mc syndrome type 1 · 3MC1 · MASP1 3MC syndrome · Michels syndrome

Data availability: 132 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › 3MC syndrome › 3MC syndrome 1

Related subtypes (2): 3MC syndrome 3, 3MC 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

132 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 34 likely benign, 17 conflicting classifications of pathogenicity, 15 benign, 12 benign/likely benign, 12 pathogenic, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
832891	NC_000003.11:g.(?186256465)(187009440_?)del	ADIPOQ	Pathogenic	criteria provided, single submitter
531899	NC_000003.11:g.(?186256465)(186980528_?)del	EIF4A2	Pathogenic	criteria provided, single submitter
30074	NM_139125.4(MASP1):c.1489C>T (p.His497Tyr)	MASP1	Pathogenic	no assertion criteria provided
30075	NM_139125.4(MASP1):c.1888T>C (p.Cys630Arg)	MASP1	Pathogenic	no assertion criteria provided
30076	NM_139125.4(MASP1):c.1997G>A (p.Gly666Glu)	MASP1	Pathogenic	no assertion criteria provided
30077	NM_139125.4(MASP1):c.2059G>A (p.Gly687Arg)	MASP1	Pathogenic	no assertion criteria provided
30078	NM_139125.4(MASP1):c.870G>A (p.Trp290Ter)	MASP1	Pathogenic	no assertion criteria provided
4804007	NM_139125.4(MASP1):c.1009A>T (p.Lys337Ter)	MASP1	Pathogenic	criteria provided, single submitter
572584	NM_139125.4(MASP1):c.812dup (p.Ser272fs)	MASP1	Pathogenic	criteria provided, single submitter
650705	NC_000003.12:g.(?187235664)(187256880_?)del	MASP1	Pathogenic	criteria provided, single submitter
807629	NM_139125.4(MASP1):c.518del (p.Ile173fs)	MASP1	Pathogenic	criteria provided, single submitter
981738	NM_139125.4(MASP1):c.913C>T (p.Gln305Ter)	MASP1	Pathogenic	no assertion criteria provided
1723297	NM_001879.6(MASP1):c.1498del (p.Asp500fs)	MASP1	Likely pathogenic	criteria provided, single submitter
4277918	NM_139125.4(MASP1):c.1889G>T (p.Cys630Phe)	MASP1	Likely pathogenic	criteria provided, single submitter
4291886	NM_139125.4(MASP1):c.2059G>C (p.Gly687Arg)	MASP1	Likely pathogenic	criteria provided, single submitter
931653	NM_001879.6(MASP1):c.1809+1G>A	MASP1	Likely pathogenic	criteria provided, single submitter
931999	NM_139125.4(MASP1):c.992_993del (p.Thr331fs)	MASP1	Likely pathogenic	criteria provided, single submitter
932000	NM_139125.4(MASP1):c.1492dup (p.Val498fs)	MASP1	Likely pathogenic	criteria provided, single submitter
1176166	NM_139125.4(MASP1):c.1352T>C (p.Ile451Thr)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191186	NM_139125.4(MASP1):c.1576C>T (p.Arg526Ter)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2136249	NM_139125.4(MASP1):c.1708A>G (p.Met570Val)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2654344	NM_001879.6(MASP1):c.1770del (p.Lys591fs)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282142	NM_139125.4(MASP1):c.501C>G (p.Ser167=)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285534	NM_139125.4(MASP1):c.863G>A (p.Arg288Gln)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286640	NM_139125.4(MASP1):c.674A>G (p.Asn225Ser)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286762	NM_139125.4(MASP1):c.1125C>T (p.His375=)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392926	NM_139125.4(MASP1):c.1136C>T (p.Thr379Ile)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499960	NM_139125.4(MASP1):c.1143T>C (p.Ser381=)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
595055	NM_139125.4(MASP1):c.1521G>A (p.Thr507=)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
595066	NM_139125.4(MASP1):c.1773C>T (p.Ala591=)	MASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
MASP1	Definitive	Autosomal recessive	3MC syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MASP1	Orphanet:293843	3MC syndrome
EIF4A2	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MASP1	HGNC:6901	ENSG00000127241	P48740	Mannan-binding lectin serine protease 1	gencc,clinvar
ADIPOQ	HGNC:13633	ENSG00000181092	Q15848	Adiponectin	clinvar
EIF4A2	HGNC:3284	ENSG00000156976	Q14240	Eukaryotic initiation factor 4A-II	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MASP1	Mannan-binding lectin serine protease 1	Precursor of a serum protease that activates the complement pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.
ADIPOQ	Adiponectin	Important adipokine involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities.
EIF4A2	Eukaryotic initiation factor 4A-II	ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MASP1	Protease	yes	3.4.21.B7	Sushi_SCR_CCP_dom, EGF, CUB_dom
ADIPOQ	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
EIF4A2	Other/Unknown	no		RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
endocervix	1
right lobe of liver	1
pericardium	1
skin of hip	1
synovial joint	1
cerebellar vermis	1
endothelial cell	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MASP1	204	broad	marker	endocervix, right lobe of liver, apex of heart
ADIPOQ	171	tissue_specific	yes	synovial joint, pericardium, skin of hip
EIF4A2	295	ubiquitous	marker	secondary oocyte, endothelial cell, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF4A2	4,842
ADIPOQ	3,816
MASP1	58

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MASP1	P48740	9
ADIPOQ	Q15848	3
EIF4A2	Q14240	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ficolins bind to repetitive carbohydrate structures on the target cell surface	1	761.3×	0.023	MASP1
Creation of C4 and C2 activators	1	634.4×	0.023	MASP1
AMPK inhibits chREBP transcriptional activation activity	1	475.8×	0.023	ADIPOQ
Lectin pathway of complement activation	1	423.0×	0.023	MASP1
Z-decay: degradation of maternal mRNAs by zygotically expressed factors	1	317.2×	0.024	EIF4A2
Complement cascade	1	211.5×	0.024	MASP1
Initial triggering of complement	1	200.3×	0.024	MASP1
Scavenging by Class A Receptors	1	200.3×	0.024	MASP1
Binding and Uptake of Ligands by Scavenger Receptors	1	181.3×	0.024	MASP1
Deadenylation of mRNA	1	146.4×	0.027	EIF4A2
M-decay: degradation of maternal mRNAs by maternally stored factors	1	108.8×	0.031	EIF4A2
Dengue Virus Genome Translation and Replication	1	105.7×	0.031	EIF4A2
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1	90.6×	0.033	EIF4A2
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	71.8×	0.036	ADIPOQ
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	65.6×	0.036	ADIPOQ
Translation initiation complex formation	1	63.4×	0.036	EIF4A2
Ribosomal scanning and start codon recognition	1	63.4×	0.036	EIF4A2
Integration of energy metabolism	1	58.6×	0.037	ADIPOQ
Adipogenesis	1	52.1×	0.037	ADIPOQ
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.037	ADIPOQ
ISG15 antiviral mechanism	1	50.1×	0.037	EIF4A2
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.041	ADIPOQ
SARS-CoV-2-host interactions	1	39.6×	0.042	MASP1
L13a-mediated translational silencing of Ceruloplasmin expression	1	33.7×	0.046	EIF4A2
GTP hydrolysis and joining of the 60S ribosomal subunit	1	33.4×	0.046	EIF4A2
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	29.7×	0.050	MASP1
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.051	ADIPOQ
SARS-CoV-2 Infection	1	26.8×	0.051	MASP1
Epigenetic regulation of gene expression	1	23.8×	0.056	ADIPOQ
SARS-CoV Infections	1	18.5×	0.069	MASP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of myeloid cell apoptotic process	1	5617.3×	0.002	ADIPOQ
negative regulation of RNA-dependent RNA polymerase activity	1	5617.3×	0.002	EIF4A2
positive regulation of glycogen (starch) synthase activity	1	5617.3×	0.002	ADIPOQ
positive regulation of metanephric podocyte development	1	5617.3×	0.002	ADIPOQ
positive regulation of renal albumin absorption	1	5617.3×	0.002	ADIPOQ
negative regulation of metanephric mesenchymal cell migration	1	5617.3×	0.002	ADIPOQ
detection of oxidative stress	1	2808.7×	0.003	ADIPOQ
negative regulation of platelet-derived growth factor receptor-alpha signaling pathway	1	2808.7×	0.003	ADIPOQ
negative regulation of cholesterol import	1	1872.4×	0.004	ADIPOQ
response to linoleic acid	1	1872.4×	0.004	ADIPOQ
response to sucrose	1	1123.5×	0.005	ADIPOQ
negative regulation of complement activation	1	1123.5×	0.005	MASP1
positive regulation of fatty acid metabolic process	1	1123.5×	0.005	ADIPOQ
negative regulation of granulocyte differentiation	1	702.2×	0.006	ADIPOQ
adiponectin-activated signaling pathway	1	702.2×	0.006	ADIPOQ
negative regulation of macrophage differentiation	1	702.2×	0.006	ADIPOQ
negative regulation of platelet-derived growth factor receptor signaling pathway	1	624.1×	0.006	ADIPOQ
negative regulation of heterotypic cell-cell adhesion	1	624.1×	0.006	ADIPOQ
negative regulation of hormone secretion	1	624.1×	0.006	ADIPOQ
negative regulation of receptor-mediated endocytosis	1	624.1×	0.006	ADIPOQ
complement activation, lectin pathway	1	561.7×	0.006	MASP1
negative regulation of synaptic transmission	1	561.7×	0.006	ADIPOQ
negative regulation of vascular associated smooth muscle cell migration	1	561.7×	0.006	ADIPOQ
cytoplasmic translational initiation	1	468.1×	0.006	EIF4A2
negative regulation of MAP kinase activity	1	468.1×	0.006	ADIPOQ
positive regulation of signal transduction	1	432.1×	0.006	ADIPOQ
negative regulation of macrophage derived foam cell differentiation	1	432.1×	0.006	ADIPOQ
cellular response to epinephrine stimulus	1	432.1×	0.006	ADIPOQ
positive regulation of monocyte chemotactic protein-1 production	1	401.2×	0.006	ADIPOQ
fatty acid oxidation	1	351.1×	0.007	ADIPOQ

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF4A2	1	2
MASP1	0	0
ADIPOQ	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	EIF4A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EIF4A2	10	Binding:10
MASP1	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MASP1	3.4.21.B7

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	EIF4A2

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	EIF4A2
C	Druggable family + PDB, no drug	1	MASP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ADIPOQ

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)
MASP1	4	—
ADIPOQ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.