immunodeficiency due to MASP-2 deficiency

Summary

immunodeficiency due to MASP-2 deficiency (MONDO:0013423) is a disease caused by MASP2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MASP2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 78

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency due to MASP-2 deficiency
Mondo ID	MONDO:0013423
MeSH	C565360
OMIM	613791
Orphanet	331187
UMLS	C3151085
MedGen	462435
GARD	0017512
Is cancer (heuristic)	no

Also known as: immunodeficiency due to MASP-2 deficiency

Data availability: 78 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › complement deficiency › disorder of lectin complement activation pathway › immunodeficiency due to MASP-2 deficiency

Related subtypes (2): immunodeficiency due to ficolin3 deficiency, mannose-binding lectin deficiency

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

78 retrieved; paginated sample, class counts are floors:

47 uncertain significance, 10 conflicting classifications of pathogenicity, 10 benign, 6 benign/likely benign, 3 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1678096	NM_006610.4(MASP2):c.1126C>T (p.Arg376Ter)	MASP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4279079	NM_006610.4(MASP2):c.716C>G (p.Thr239Ser)	MASP2	Likely pathogenic	no assertion criteria provided
1696493	NM_006610.4(MASP2):c.741+1G>T	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291784	NM_006610.4(MASP2):c.1142C>T (p.Thr381Ile)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291788	NM_006610.4(MASP2):c.1064A>T (p.Asp355Val)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291792	NM_006610.4(MASP2):c.828C>G (p.Ile276Met)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291802	NM_006610.4(MASP2):c.467G>A (p.Cys156Tyr)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291806	NM_006610.4(MASP2):c.383C>T (p.Thr128Met)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291811	NM_006610.4(MASP2):c.231C>T (p.Val77=)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5210	NM_006610.4(MASP2):c.359A>G (p.Asp120Gly)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874902	NM_006610.4(MASP2):c.352C>T (p.Arg118Cys)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
992550	NM_006610.4(MASP2):c.263C>T (p.Thr88Met)	MASP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032464	NM_006610.4(MASP2):c.1078G>A (p.Ala360Thr)	MASP2	Uncertain significance	criteria provided, single submitter
1032465	NM_006610.4(MASP2):c.503G>A (p.Arg168His)	MASP2	Uncertain significance	criteria provided, single submitter
1342490	NM_006610.4(MASP2):c.890-1G>A	MASP2	Uncertain significance	criteria provided, single submitter
2433647	NM_006610.4(MASP2):c.1719G>C (p.Trp573Cys)	MASP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689402	NM_006610.4(MASP2):c.1903G>A (p.Gly635Arg)	MASP2	Uncertain significance	criteria provided, single submitter
2689403	NM_006610.4(MASP2):c.1254_1261delinsCCTCACACACTC (p.Trp418fs)	MASP2	Uncertain significance	criteria provided, single submitter
291776	NM_006610.4(MASP2):c.*111C>T	MASP2	Uncertain significance	criteria provided, single submitter
291787	NM_006610.4(MASP2):c.1080G>A (p.Ala360=)	MASP2	Uncertain significance	criteria provided, single submitter
291789	NM_006610.4(MASP2):c.967A>C (p.Ser323Arg)	MASP2	Uncertain significance	criteria provided, single submitter
291793	NM_006610.4(MASP2):c.808A>C (p.Lys270Gln)	MASP2	Uncertain significance	criteria provided, single submitter
291796	NM_006610.4(MASP2):c.661T>C (p.Phe221Leu)	MASP2	Uncertain significance	criteria provided, single submitter
291800	NM_006610.4(MASP2):c.507A>G (p.Ala169=)	MASP2	Uncertain significance	criteria provided, single submitter
291803	NM_006610.4(MASP2):c.420C>T (p.Asp140=)	MASP2	Uncertain significance	criteria provided, single submitter
291804	NM_006610.4(MASP2):c.395C>T (p.Ala132Val)	MASP2	Uncertain significance	criteria provided, single submitter
291810	NM_006610.4(MASP2):c.234+6G>A	MASP2	Uncertain significance	criteria provided, single submitter
291812	NM_006610.4(MASP2):c.159C>T (p.Pro53=)	MASP2	Uncertain significance	criteria provided, single submitter
291813	NM_006610.4(MASP2):c.93A>T (p.Ala31=)	MASP2	Uncertain significance	criteria provided, single submitter
291814	NM_006610.4(MASP2):c.81C>T (p.Phe27=)	MASP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 4 · 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
MASP2	Strong	Autosomal recessive	immunodeficiency due to MASP-2 deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MASP2	Orphanet:331187	Immunodeficiency due to MASP-2 deficiency
TARDBP	Orphanet:275872	Frontotemporal dementia with motor neuron disease
TARDBP	Orphanet:700154	TARDBP-related predominantly upper-limb distal myopathy
TARDBP	Orphanet:803	Amyotrophic lateral sclerosis

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
MASP2	HGNC:6902	ENSG00000009724	O00187	Mannan-binding lectin serine protease 2	gencc,clinvar
TARDBP	HGNC:11571	ENSG00000120948	Q13148	TAR DNA-binding protein 43	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MASP2	Mannan-binding lectin serine protease 2	Precursor of a serum protease that activates the lectin 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.
TARDBP	TAR DNA-binding protein 43	RNA-binding protein that is involved in various steps of RNA biogenesis and processing.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MASP2	Protease	yes	3.4.21.104	EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
TARDBP	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf

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
cerebellar hemisphere	1
liver	1
right lobe of liver	1
ganglionic eminence	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MASP2	172	tissue_specific	marker	right lobe of liver, liver, cerebellar hemisphere
TARDBP	301	ubiquitous	marker	secondary oocyte, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TARDBP	7,245
MASP2	1,321

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TARDBP	Q13148	44
MASP2	O00187	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Ficolins bind to repetitive carbohydrate structures on the target cell surface	1	2284.0×	0.002	MASP2
Lectin pathway of complement activation	1	1268.9×	0.002	MASP2
Initial triggering of complement	1	601.0×	0.002	MASP2
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.011	MASP2

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
nuclear inner membrane organization	1	8426.0×	0.002	TARDBP
complement activation, lectin pathway	1	842.6×	0.010	MASP2
host-mediated suppression of viral transcription	1	648.1×	0.010	TARDBP
3’-UTR-mediated mRNA destabilization	1	383.0×	0.010	TARDBP
3’-UTR-mediated mRNA stabilization	1	351.1×	0.010	TARDBP
amyloid fibril formation	1	300.9×	0.010	TARDBP
negative regulation of protein phosphorylation	1	290.6×	0.010	TARDBP
complement activation, classical pathway	1	271.8×	0.010	MASP2
positive regulation of protein import into nucleus	1	210.7×	0.011	TARDBP
regulation of circadian rhythm	1	129.6×	0.014	TARDBP
positive regulation of insulin secretion	1	127.7×	0.014	TARDBP
rhythmic process	1	125.8×	0.014	TARDBP
response to endoplasmic reticulum stress	1	83.4×	0.019	TARDBP
regulation of protein stability	1	62.9×	0.024	TARDBP
RNA splicing	1	44.1×	0.029	TARDBP
regulation of gene expression	1	41.7×	0.029	TARDBP
regulation of apoptotic process	1	41.7×	0.029	TARDBP
mRNA processing	1	39.4×	0.029	TARDBP
regulation of cell cycle	1	37.3×	0.029	TARDBP
negative regulation of gene expression	1	34.5×	0.030	TARDBP
proteolysis	1	17.1×	0.058	MASP2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TARDBP	MITOXANTRONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TARDBP	1	4
MASP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MITOXANTRONE	4	TARDBP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MASP2	9	Binding:9
TARDBP	8	Binding:7, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MASP2	3.4.21.104	mannan-binding lectin-associated serine protease-2

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)
MITOXANTRONE	4	TARDBP

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TARDBP
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MASP2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
MASP2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.