hyper-IgM syndrome type 2

Summary

hyper-IgM syndrome type 2 (MONDO:0011528) is a disease caused by AICDA (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: AICDA (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 280

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgM syndrome type 2
Mondo ID	MONDO:0011528
OMIM	605258
Orphanet	101089
DOID	DOID:0060758
NCIT	C129074
SNOMED CT	403836001
UMLS	C1720956
MedGen	354548
GARD	0010578
Is cancer (heuristic)	no

Also known as: Activation-induced cytidine deaminase deficiency · activation-induced cytidine deaminase deficiency · AICDA hyper-IgM syndrome · aid deficiency · HIGM2 · hyper IgM syndrome 2 · hyper-IgM syndrome caused by mutation in AICDA · hyper-IgM syndrome type 2 · immunodeficiency with hyper IgM type 2 · immunodeficiency with hyper-IgM, type 2

Data availability: 280 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › hyperimmunoglobulin syndrome › hyper-IgM syndrome › hyper-IgM syndrome type 2

Related subtypes (4): hyper-IgM syndrome type 1, hyper-IgM syndrome type 3, hyper-IgM syndrome type 5, hyper-IgM syndrome type 4

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

280 retrieved; paginated sample, class counts are floors:

128 uncertain significance, 87 likely benign, 20 pathogenic, 18 benign, 11 likely pathogenic, 7 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1683704	NM_020661.4(AICDA):c.403C>T (p.Gln135Ter)	AICDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191031	NM_020661.4(AICDA):c.169G>A (p.Val57Met)	AICDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137297	NM_020661.4(AICDA):c.93C>A (p.Tyr31Ter)	AICDA	Pathogenic	criteria provided, single submitter
2691321	NM_020661.4(AICDA):c.295C>T (p.Arg99Ter)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
3244289	NC_000012.11:g.(?8756880)(8765363_?)del	AICDA	Pathogenic	criteria provided, single submitter
3244290	NC_000012.11:g.(?8765336)(8765363_?)del	AICDA	Pathogenic	criteria provided, single submitter
35655	NM_020661.4(AICDA):c.251G>A (p.Trp84Ter)	AICDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
379250	NM_020661.4(AICDA):c.334C>T (p.Arg112Cys)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
4725936	NM_020661.4(AICDA):c.408dup (p.Ala137fs)	AICDA	Pathogenic	criteria provided, single submitter
4732297	NM_020661.4(AICDA):c.342C>A (p.Tyr114Ter)	AICDA	Pathogenic	criteria provided, single submitter
5122	NM_020661.4(AICDA):c.70C>T (p.Arg24Trp)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
5123	NM_020661.4(AICDA):c.203G>A (p.Trp68Ter)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
5125	NM_020661.4(AICDA):c.317T>C (p.Leu106Pro)	AICDA	Pathogenic	no assertion criteria provided
5126	NM_020661.4(AICDA):c.415A>G (p.Met139Val)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
5127	NM_020661.4(AICDA):c.441C>A (p.Cys147Ter)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
5128	NM_020661.4(AICDA):c.452T>C (p.Phe151Ser)	AICDA	Pathogenic	no assertion criteria provided
5129	NM_020661.4(AICDA):c.22_40del (p.Arg8fs)	AICDA	Pathogenic	no assertion criteria provided
5130	NM_020661.4(AICDA):c.177_185del (p.Leu59_Leu62delinsPhe)	AICDA	Pathogenic	no assertion criteria provided
617969	NM_020661.4(AICDA):c.259T>C (p.Cys87Arg)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
636339	NM_020661.4(AICDA):c.416T>C (p.Met139Thr)	AICDA	Pathogenic	criteria provided, multiple submitters, no conflicts
657907	NC_000012.12:g.(?8604264)(8612787_?)del	AICDA	Pathogenic	criteria provided, single submitter
804464	NM_020661.4(AICDA):c.274C>T (p.Arg92Ter)	AICDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
806827	NM_020661.4(AICDA):c.568C>T (p.Arg190Ter)	AICDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
939010	NM_020661.4(AICDA):c.260G>C (p.Cys87Ser)	AICDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
950412	NM_020661.4(AICDA):c.338T>C (p.Leu113Pro)	AICDA	Pathogenic	criteria provided, single submitter
831306	NC_000012.12:g.(?8456112)(8612767_?)del	CLEC6A	Pathogenic	criteria provided, single submitter
322029	NM_012452.3(TNFRSF13B):c.204dup (p.Leu69fs)	TNFRSF13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1473761	NM_020661.4(AICDA):c.544-2A>G	AICDA	Likely pathogenic	criteria provided, single submitter
1683705	NM_020661.4(AICDA):c.45C>G (p.Phe15Leu)	AICDA	Likely pathogenic	criteria provided, single submitter
1931360	NM_020661.4(AICDA):c.427+1G>A	AICDA	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
AICDA	Definitive	Autosomal recessive	hyper-IgM syndrome type 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AICDA	Orphanet:101089	Hyper-IgM syndrome type 2
TNFRSF13B	Orphanet:696907	Common variable immunodeficiency phenotype due to homozygous TACI deficiency

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
AICDA	HGNC:13203	ENSG00000111732	Q9GZX7	Single-stranded DNA cytosine deaminase	gencc,clinvar
CLEC6A	HGNC:14556	ENSG00000205846	Q6EIG7	C-type lectin domain family 6 member A	clinvar
TNFRSF13B	HGNC:18153	ENSG00000240505	O14836	Tumor necrosis factor receptor superfamily member 13B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AICDA	Single-stranded DNA cytosine deaminase	Single-stranded DNA-specific cytidine deaminase.
CLEC6A	C-type lectin domain family 6 member A	Calcium-dependent lectin that acts as a pattern recognition receptor (PRR) of the innate immune system: specifically recognizes and binds alpha-mannans on C.albicans hypheas.
TNFRSF13B	Tumor necrosis factor receptor superfamily member 13B	Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity.

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AICDA	Enzyme (other)	yes	3.5.4.38	CMP_dCMP_dom, AID, APOBEC/CMP_deaminase_Zn-bd
CLEC6A	Other/Unknown	no		C-type_lectin-like, C-type_lectin-like/link_sf, CTDL_fold
TNFRSF13B	Other/Unknown	no		TACI_Cys-rich-dom, TNFR_13B

Expression context

Cohort genes with no expression data: 0.

3 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
male germ line stem cell (sensu Vertebrata) in testis	2
buccal mucosa cell	1
lymph node	1
leukocyte	1
monocyte	1
olfactory bulb	1
spleen	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AICDA	121	tissue_specific	marker	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, lymph node
CLEC6A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, monocyte, leukocyte
TNFRSF13B	158	tissue_specific	marker	type B pancreatic cell, olfactory bulb, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AICDA	2,195
TNFRSF13B	1,333
CLEC6A	968

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AICDA	Q9GZX7	5
CLEC6A	Q6EIG7	2
TNFRSF13B	O14836	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Maternal to zygotic transition (MZT)	1	237.9×	0.013	AICDA
Dectin-2 family	1	141.0×	0.013	CLEC6A
TNFs bind their physiological receptors	1	131.3×	0.013	TNFRSF13B
Chromatin modifications during the maternal to zygotic transition (MZT)	1	54.4×	0.023	AICDA
Developmental Biology	1	4.8×	0.194	AICDA

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
detection of yeast	1	2808.7×	0.004	CLEC6A
somatic diversification of immunoglobulins	1	2808.7×	0.004	AICDA
adaptive immune response	2	56.2×	0.004	CLEC6A, TNFRSF13B
regulation of nuclear cell cycle DNA replication	1	1123.5×	0.006	AICDA
response to yeast	1	702.2×	0.007	CLEC6A
DNA cytosine deamination	1	624.1×	0.007	AICDA
negative regulation of single stranded viral RNA replication via double stranded DNA intermediate	1	510.7×	0.007	AICDA
cytidine to uridine editing	1	468.1×	0.007	AICDA
positive regulation of T-helper 17 type immune response	1	468.1×	0.007	CLEC6A
positive regulation of gene expression via chromosomal CpG island demethylation	1	401.2×	0.007	AICDA
somatic hypermutation of immunoglobulin genes	1	351.1×	0.007	AICDA
negative regulation of B cell proliferation	1	312.1×	0.007	TNFRSF13B
antifungal innate immune response	1	312.1×	0.007	CLEC6A
isotype switching	1	280.9×	0.007	AICDA
stimulatory C-type lectin receptor signaling pathway	1	244.2×	0.008	CLEC6A
positive regulation of intracellular signal transduction	1	216.1×	0.008	CLEC6A
B cell homeostasis	1	187.2×	0.009	TNFRSF13B
defense response to fungus	1	147.8×	0.010	CLEC6A
positive regulation of cytokine production	1	90.6×	0.016	CLEC6A
hematopoietic progenitor cell differentiation	1	79.1×	0.018	TNFRSF13B
B cell differentiation	1	73.0×	0.018	AICDA
defense response to bacterium	1	36.0×	0.035	AICDA
cellular response to lipopolysaccharide	1	32.7×	0.037	AICDA
mRNA processing	1	26.2×	0.044	AICDA
positive regulation of canonical NF-kappaB signal transduction	1	24.2×	0.046	CLEC6A
defense response to virus	1	23.1×	0.046	AICDA
cell surface receptor signaling pathway	1	21.4×	0.048	TNFRSF13B
innate immune response	1	11.2×	0.087	CLEC6A

Therapeutics

Drug target analysis

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

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
AICDA	0	0
CLEC6A	0	0
TNFRSF13B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CLEC6A	2	Binding:2
AICDA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AICDA	3.5.4.38	single-stranded DNA cytosine deaminase

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

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	1	AICDA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CLEC6A, TNFRSF13B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AICDA	1	—
CLEC6A	2	—
TNFRSF13B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.