AICDA

Summary

AICDA (activation induced cytidine deaminase, HGNC:13203) is a protein-coding gene on chromosome 12p13.31, encoding Single-stranded DNA cytosine deaminase (Q9GZX7). Single-stranded DNA-specific cytidine deaminase.

This gene encodes a RNA-editing deaminase that is a member of the cytidine deaminase family. AICDA is specifically expressed and active in germinal center-like B cells. In the germinal center, AICDA is involved in somatic hypermutation, gene conversion, and class-switch recombination of immunoglobulin genes. An epigenetic role in neoplastic transformation and lymphoma progression has been experimentally ascribed to AICDA using mouse models. Defects in this gene are the cause of autosomal recessive hyper-IgM immunodeficiency syndrome type 2 (HIGM2).

Source: NCBI Gene 57379 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyper-IgM syndrome type 2 (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 301 total — 19 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_020661

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13203
Approved symbol	AICDA
Name	activation induced cytidine deaminase
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	HIGM2, CDA2, ARP2, AID
Ensembl gene	ENSG00000111732
Ensembl biotype	protein_coding
OMIM	605257
Entrez	57379

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 retained_intron

ENST00000229335, ENST00000537228, ENST00000543081, ENST00000544516, ENST00000545576, ENST00000696246, ENST00000696271, ENST00000696272, ENST00000696273

RefSeq mRNA: 3 — MANE Select: NM_020661 NM_001330343, NM_001410970, NM_020661

CCDS: CCDS41747, CCDS81662, CCDS91650

Canonical transcript exons

ENST00000229335 — 5 exons

Exon	Start	End
ENSE00000717136	8604807	8604922
ENSE00000717137	8605215	8605485
ENSE00001181366	8602170	8604337
ENSE00002235754	8612760	8612859
ENSE00003596810	8606865	8607012

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 79.66.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2396 / max 125.9335, expressed in 44 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129342	0.1359	25
129339	0.0579	19
129341	0.0163	7
129338	0.0158	8
129340	0.0136	7

Top tissues by expression

272 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	79.66	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.29	gold quality
lymph node	UBERON:0000029	71.57	gold quality
vermiform appendix	UBERON:0001154	69.87	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.36	gold quality
caecum	UBERON:0001153	66.17	gold quality
tonsil	UBERON:0002372	65.52	gold quality
ileal mucosa	UBERON:0000331	63.98	silver quality
nasopharynx	UBERON:0001728	62.06	silver quality
epithelium of nasopharynx	UBERON:0001951	62.06	silver quality
placenta	UBERON:0001987	59.61	gold quality
mucosa of stomach	UBERON:0001199	53.79	gold quality
superior surface of tongue	UBERON:0007371	52.39	gold quality
myocardium	UBERON:0002349	51.72	gold quality
deltoid	UBERON:0001476	51.61	gold quality
gall bladder	UBERON:0002110	51.40	gold quality
left ventricle myocardium	UBERON:0006566	51.17	gold quality
cardiac muscle of right atrium	UBERON:0003379	51.07	gold quality
small intestine Peyer’s patch	UBERON:0003454	51.04	gold quality
colonic epithelium	UBERON:0000397	50.67	gold quality
epithelial cell of pancreas	CL:0000083	50.64	gold quality
quadriceps femoris	UBERON:0001377	50.60	gold quality
upper arm skin	UBERON:0004263	50.47	gold quality
thymus	UBERON:0002370	50.46	gold quality
nasal cavity epithelium	UBERON:0005384	50.01	gold quality
small intestine	UBERON:0002108	49.75	gold quality
vastus lateralis	UBERON:0001379	49.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
tibialis anterior	UBERON:0001385	49.21	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ESR1, FOXO1, HOXC4, ID2, IKZF3, IL13, IL4, IRF4, PAX5, SPI1, TCF3

miRNA regulators (miRDB)

88 targeting AICDA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• required for somatic hypermutation in the centroblast-like Ramos cells; sufficient to induce somatic hypermutation in hybridoma cells, which represent a later stage of B-cell differentiation that does not normally undergo SHM (PMID:11823785)
• AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. (PMID:12097915)
• Internal IgH class switch region deletions are position-independent and enhanced by expression (PMID:12114543)
• Somatic hypermutation of the AID transgene in B and non-B cells (PMID:12202747)
• AID is highly regulated during normal B-cell development & is constitutively expressed in human germinal center B-NHL & in subsets of nongerminal center B-NHL. This constitutive expression may cause illegitimate recombination & somatic mutation in B-NHL. (PMID:12511417)
• Chronic lymphocytic leukemia B cells that express this enzyme display dissociation between class switch recombination and somatic hypermutation (PMID:12521993)
• has the function to induce spontaneous IgM production in B cells (PMID:12715918)
• Activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations. (PMID:12799424)
• data suggest that AID-mediated DNA alterations may occur in a variably sized, minor subset of B-CLL cells at any given time. (PMID:12855567)
• Expression of activation-induced cytidine deaminase is confined to B-cell non-Hodgkin’s lymphomas of germinal-center phenotype. (PMID:12873980)
• Activation-induced cytidine deaminase plays a crucial role in the induction of DNA breakage during immunoglobulin class switch recombination. (PMID:12928399)
• there is an essential role for the C-terminal domain of AID in CSR that is independent of its cytidine deaminase activity and that is not required for either gene conversion or somatic hypermutation (PMID:14536088)
• AID transcripts, including a splice variant, were common to both unmutated or mutated VH genes in mantle cell lymphoma. (PMID:14551145)
• AID is a nucleocytoplasmic shuttling protein with a bipartite nuclear localization signal and a nuclear export signal in its N and C termini, respectively (PMID:14769937)
• AID expression was associated with the ongoing mutation in follicular lymphoma (FL) fresh cells. Results suggest the switch off of AID expression may start in the B-lineage differentiation stage counterpart of FL after optimizing somatic hypermutation (PMID:14990977)
• expression of AID in 15 Burkitt’s lymphoma cell lines by RT-PCR (PMID:15061213)
• Activation-induced cytosine deaminase (AID) is actively exported out of the nucleus but retained by the induction of DNA breaks (PMID:15087440)
• results suggested both AID and APOBEC-1 are equally likely to bind single-stranded DNA or RNA, which has implications for the identification of natural AID targets (PMID:15148397)
• separate domains of AID interact with specific cofactors to regulate these two distinct genetic events in a target-specific way (PMID:15195091)
• AID protein is specifically expressed in normal and transformed germinal center B cells (PMID:15304391)
• wild type AID retains its specificity for mutated hot spot motifs within the confines of a moving transcription bubble while introducing clusters of multiple deaminations predominantly on the nontranscribed strand (PMID:15371439)
• novel mutation found in the gene encoding for activation-induced cytidine deaminase in a Tunisian family with hyper-IgM type 2 syndrome (PMID:15372234)
• Aid and perhaps some of its family members may have roles in epigenetic reprogramming (PMID:15448152)
• AID overexpression by itself does not automatically lead to the onset of a mutator phenotype. (PMID:15593119)
• expression in acute lymphoblastic leukemia L2 with t(14;18)(q32;q21) (PMID:15613101)
• Direct evidence is presented for the DNA deamination from Escherichia coli expressing AID; uracils are preferentially generated at cytosines in the nontranscribed strand during transcription. (PMID:15944282)
• AID-mediated deamination of DNA is a major cause of mutations at G-C base pairs in immunoglobulin genes during somatic hypermutation. Its intrinsic substrate specificity is a primary determinant of mutational hotspots at G-C base pairs during SHM. (PMID:15949042)
• AID can interact with MDM2, an oncoprotein that shuttles between the nucleus and the cytoplasm and targets p53 for nuclear export and degradation. (PMID:16122802)
• interfollicular large B cells and AID-expressing B lymphocytes of the thymic medulla could give rise to mature B-cell malignancies. (PMID:16269615)
• Somatic hypermutation on both DNA strands is the natural outcome of AID action on a transcribed gene. (PMID:16314506)
• control of T cell-dependent immune responses may be modulated, via AID, by signals that activate protein kinase A (PMID:16387847)
• The distribution of nuclear AID is consistent with the topography of somatic hypermutation and class switch recombination in activated B cells. (PMID:16439679)
• The AID expression and ASHM are associated with higher-grade transformation of CLL and provide further evidences that AID expression and ASHM may be activated during the clonal history of B-cell lymphomas. (PMID:16541139)
• review of the role of AICDA in producing high affinity isotype-switched antibodies [review] (PMID:16624806)
• AID binds DNA exposed by the transcribing polymerase, implicating the polymerase itself as the vehicle which distributes AID on DNA as it moves away from the promoter. (PMID:16705187)
• Features of activation-induced deaminase (AID) mapping within the noncatalytic domain, but outside the chromosome region maintenance 1-dependent nuclear export signal at the C-terminus, influence its function. (PMID:16785531)
• APOBEC3G is not a nucleo-cytoplasmic shuttling protein like APOBEC-1 and AID (PMID:16999936)
• AID may persist on immunoglobulin and other target sequences after deamination, possibly acting as a scaffolding protein to recruit other factors (PMID:17060445)
• Findings suggest that the aberrant expression of AID is observed in human hepatocytes with several pathological settings, including chronic liver disease and hepatocellular carcinoma. (PMID:17066440)
• cells may be the founder cells of the germinal center reaction (a pro-GC cell) and may be the normal counterpart of the mantle cell lymphoma cell (PMID:17132718)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aicda	ENSDARG00000015734
mus_musculus	Aicda	ENSMUSG00000040627
rattus_norvegicus	Aicda	ENSRNOG00000015478

Paralogs (9): APOBEC3H (ENSG00000100298), APOBEC1 (ENSG00000111701), APOBEC2 (ENSG00000124701), APOBEC3A (ENSG00000128383), APOBEC3F (ENSG00000128394), APOBEC3B (ENSG00000179750), APOBEC3G (ENSG00000239713), APOBEC3D (ENSG00000243811), APOBEC3C (ENSG00000244509)

Protein

Protein identifiers

Single-stranded DNA cytosine deaminase — Q9GZX7 (reviewed: Q9GZX7)

Alternative names: Activation-induced cytidine deaminase, Cytidine aminohydrolase

All UniProt accessions (7): Q9GZX7, A0A8Q3SII6, A0A8Q3SIK8, A0A8Q3WL45, Q546Y9, Q6QJ80, Q6QLN7

UniProt curated annotations — full annotation on UniProt →

Function. Single-stranded DNA-specific cytidine deaminase. Involved in somatic hypermutation (SHM), gene conversion, and class-switch recombination (CSR) in B-lymphocytes by deaminating C to U during transcription of Ig-variable (V) and Ig-switch (S) region DNA. Required for several crucial steps of B-cell terminal differentiation necessary for efficient antibody responses. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation.

Subunit / interactions. Interacts with CTNNBL1; the interaction is important for the immunoglobulin switch activity of AICDA. Interacts (via its NLS) with KPNA1. Interacts with PKA/PRKACA and PRKAR1A/PKR1. Interacts with TRIM28 and NCL. Interacts with SUPT6H. Interacts with RNF126. Directly interacts with MCM3AP; this interaction may favor AICDA recruitment to immunoglobulin variable region genes, hence promoting somatic hypermutations.

Subcellular location. Nucleus. Cytoplasm. Cytosol.

Tissue specificity. Strongly expressed in lymph nodes and tonsils.

Post-translational modifications. Ser-38 is the major site whereas Thr-27 is the minor site of phosphorylation. Phosphorylation regulates its class-switch recombination activity. Probably monoubiquitinated on several residues by RNF126.

Disease relevance. Immunodeficiency with hyper-IgM 2 (HIGM2) [MIM:605258] A rare immunodeficiency syndrome characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE. It results in a profound susceptibility to bacterial infections. The disease is caused by variants affecting the gene represented in this entry.

Induction. Negatively regulated by microRNA-155 (miR-155).

Similarity. Belongs to the cytidine and deoxycytidylate deaminase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9GZX7-1	1	yes
Q9GZX7-2	2

RefSeq proteins (3): NP_001317272, NP_001397899, NP_065712* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002125	CMP_dCMP_dom	Domain
IPR013158	AID	Domain
IPR016192	APOBEC/CMP_deaminase_Zn-bd	Binding_site
IPR016193	Cytidine_deaminase-like	Homologous_superfamily
IPR050610	APOBEC_Cyt_Deaminase	Family

Pfam: PF08210

Enzyme classification (BRENDA):

• EC 3.5.4.38 — single-stranded DNA cytosine deaminase (BRENDA: 8 organisms, 58 substrates, 4 inhibitors, 11 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CCCA	0.001–0.073	5
TTCA	0.001–0.019	5

Catalyzed reactions (Rhea), 1 shown:

• a 2’-deoxycytidine in single-stranded DNA + H2O + H(+) = a 2’-deoxyuridine in single-stranded DNA + NH4(+) (RHEA:50948)

UniProt features (54 total): sequence variant 12, mutagenesis site 12, strand 8, helix 6, binding site 3, region of interest 3, modified residue 2, short sequence motif 2, chain 1, domain 1, splice variant 1, sequence conflict 1, turn 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5W0R	X-RAY DIFFRACTION	2.4
5JJ4	X-RAY DIFFRACTION	2.81
5W0U	X-RAY DIFFRACTION	2.9
5W1C	X-RAY DIFFRACTION	3.18
5W0Z	X-RAY DIFFRACTION	3.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZX7-F1	88.43	0.73

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 58 (proton donor)

Ligand- & substrate-binding residues (3): 90; 56; 87

Post-translational modifications (2): 27, 38

Mutagenesis-validated functional residues (12):

Position	Phenotype
10	little effect on nuclear import; when associated with a-193. no effect on ctnnbl1 binding.
18	greatly impaired nuclear import; when associated with v-19 and a-193. reduced interaction with both ctnnbl1 and kpna1, a
19	greatly impaired nuclear import; when associated with s-18 and a-193. reduced interaction with both ctnnbl1 and kpna1, a
20	impaired nuclear import; when associated with a-193. no effect on ctnnbl1 binding.
27	loss of phosphorylation. no effect on cytidine deaminase activity. impaired class-switch recombination activity.
27	phosphomimetic mutant which shows loss of cytidine deaminase activity and impaired class-switch recombination activity.
38	loss of phosphorylation. impaired class-switch recombination activity. no effect on interaction with ctnnbl1.
38	no effect on interaction with ctnnbl1.
39–42	greatly reduced interaction with ctnnbl1 but no effect on subcellular location, enzyme activity, ability to oligomerize
50	some reduced nuclear import; when associated with a-193.
112	greatly reduced nuclear import; when associated with a-193.
193	completely abolishes nuclear import; when associated with w-24 or d-112. little affect on nuclear import; when associate

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9821002	Chromatin modifications during the maternal to zygotic transition (MZT)
R-HSA-1266738	Developmental Biology
R-HSA-9816359	Maternal to zygotic transition (MZT)

MSigDB gene sets: 214 (showing top): MODULE_169, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, GOBP_CELL_CYCLE_DNA_REPLICATION, GCANCTGNY_MYOD_Q6, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, AP4_Q6, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_NUCLEAR_CELL_CYCLE_DNA_REPLICATION, GOBP_B_CELL_MEDIATED_IMMUNITY

GO Biological Process (14): mRNA processing (GO:0006397), somatic diversification of immunoglobulins (GO:0016445), somatic hypermutation of immunoglobulin genes (GO:0016446), cytidine to uridine editing (GO:0016554), B cell differentiation (GO:0030183), regulation of nuclear cell cycle DNA replication (GO:0033262), defense response to bacterium (GO:0042742), positive regulation of gene expression via chromosomal CpG island demethylation (GO:0044029), isotype switching (GO:0045190), negative regulation of single stranded viral RNA replication via double stranded DNA intermediate (GO:0045869), defense response to virus (GO:0051607), DNA cytosine deamination (GO:0070383), cellular response to lipopolysaccharide (GO:0071222), regulation of macromolecule biosynthetic process (GO:0010556)

GO Molecular Function (10): RNA binding (GO:0003723), cytidine deaminase activity (GO:0004126), zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amidines (GO:0016814), metal ion binding (GO:0046872)

GO Cellular Component (5): P-body (GO:0000932), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Maternal to zygotic transition (MZT)	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	2
cellular anatomical structure	2
RNA processing	1
mRNA metabolic process	1
somatic diversification of immune receptors	1
immunoglobulin production	1
somatic diversification of immune receptors via somatic mutation	1
somatic diversification of immunoglobulins	1
base conversion or substitution editing	1
lymphocyte differentiation	1
B cell activation	1
regulation of cell cycle process	1
nuclear DNA replication	1
regulation of DNA-templated DNA replication	1
response to bacterium	1
transcription initiation-coupled chromatin remodeling	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
single stranded viral RNA replication via double stranded DNA intermediate	1
negative regulation of viral genome replication	1
regulation of single stranded viral RNA replication via double stranded DNA intermediate	1
negative regulation of RNA biosynthetic process	1
response to virus	1
DNA deamination	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
macromolecule biosynthetic process	1
regulation of biosynthetic process	1
regulation of macromolecule metabolic process	1
nucleic acid binding	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amidines	1
deaminase activity	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
protein binding	1
molecular_function	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

2056 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AICDA	UNG	P13051	902
AICDA	BCL6	P41182	898
AICDA	IGHV4-38-2	P0DP08	878
AICDA	APOBEC4	Q8WW27	874
AICDA	CD40LG	P29965	853
AICDA	PAX5	Q02548	851
AICDA	CTNNBL1	Q8WYA6	804
AICDA	CD40	P25942	799
AICDA	CDA	P32320	782
AICDA	PRDM1	O75626	780
AICDA	TDG	Q13569	771
AICDA	BACH2	Q9BYV9	767
AICDA	CD19	P15391	761
AICDA	RHOH	Q15669	749
AICDA	RAG1	P15918	726

IntAct

40 interactions, top by confidence:

A	B	Type	Score
AICDA	PRKAR1A	psi-mi:“MI:0915”(physical association)	0.620
AICDA	PRKAR1A	psi-mi:“MI:0914”(association)	0.620
TDG	AICDA	psi-mi:“MI:0915”(physical association)	0.580
AICDA	TDG	psi-mi:“MI:0915”(physical association)	0.580
DNAJA2	AICDA	psi-mi:“MI:0915”(physical association)	0.570
AICDA	DNAJA2	psi-mi:“MI:0914”(association)	0.570
AICDA	C	psi-mi:“MI:0915”(physical association)	0.520
AICDA	PRKACA	psi-mi:“MI:0915”(physical association)	0.500
AICDA	GADD45A	psi-mi:“MI:0915”(physical association)	0.500
AICDA	GADD45A	psi-mi:“MI:0914”(association)	0.500
GADD45A	AICDA	psi-mi:“MI:0914”(association)	0.500
DNAJA1	AICDA	psi-mi:“MI:0915”(physical association)	0.500
AICDA	DNAJA1	psi-mi:“MI:0915”(physical association)	0.500
HSPA8	AICDA	psi-mi:“MI:0915”(physical association)	0.500
AICDA	AICDA	psi-mi:“MI:0915”(physical association)	0.400
AICDA	XPO1	psi-mi:“MI:0915”(physical association)	0.400
AICDA	KPNA5	psi-mi:“MI:0915”(physical association)	0.400
AICDA	KPNA3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (99): AICDA (Reconstituted Complex), AICDA (Proximity Label-MS), AICDA (Affinity Capture-MS), AICDA (Affinity Capture-Western), AICDA (Reconstituted Complex), USP10 (Affinity Capture-MS), UCHL1 (Affinity Capture-MS), UCHL5 (Affinity Capture-MS), USP14 (Affinity Capture-MS), USP15 (Affinity Capture-MS), USP7 (Affinity Capture-MS), CTNNBL1 (Affinity Capture-MS), EXOSC2 (Affinity Capture-MS), EXOSC10 (Affinity Capture-MS), PTBP1 (Affinity Capture-MS)

ESM2 similar proteins: A2VDP6, A9QA56, G1SRW8, P0C7P3, P31941, P60704, P60705, Q08AF3, Q19Q52, Q1WBT4, Q2PT36, Q3SYR3, Q4VDN5, Q5RCA5, Q5XI89, Q68D06, Q694B4, Q694B5, Q694B6, Q694B7, Q694B8, Q694B9, Q694C0, Q694C1, Q694C2, Q694C4, Q694C5, Q6NTF7, Q75W64, Q7YR23, Q7YR24, Q7YR25, Q7Z7L1, Q8IUX4, Q8IXQ6, Q969Y0, Q96AK3, Q99J72, Q9BQQ7, Q9GZX7

Diamond homologs: A9QA56, P31941, P38483, P41238, P47855, P60704, P60705, Q19Q52, Q1WBT4, Q2PT36, Q4VDN5, Q694B3, Q694B5, Q694B6, Q694B7, Q694B8, Q694B9, Q694C0, Q694C1, Q694C2, Q694C4, Q694C5, Q6NTF7, Q75W64, Q7YR23, Q7YR24, Q7YR25, Q8IUX4, Q99J72, Q9EQP0, Q9GZX7, Q9HC16, Q9NRW3, Q9TUI7, Q9UH17, Q9WVE0, Q3SYR3, Q694B4, Q96AK3, Q9WV35

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRKACA	unknown	AICDA	phosphorylation
FBXW11	“down-regulates quantity by destabilization”	AICDA	binding
“Cullin 7-RBX1-Skp1”	“down-regulates quantity by destabilization”	AICDA	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Maturation of DENV proteins	5	70.5×	1e-06
Infectious disease	5	8.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

301 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	13
Uncertain significance	134
Likely benign	94
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2137297	NM_020661.4(AICDA):c.93C>A (p.Tyr31Ter)	Pathogenic
2691321	NM_020661.4(AICDA):c.295C>T (p.Arg99Ter)	Pathogenic
3244289	NC_000012.11:g.(?8756880)(8765363_?)del	Pathogenic
3244290	NC_000012.11:g.(?8765336)(8765363_?)del	Pathogenic
379250	NM_020661.4(AICDA):c.334C>T (p.Arg112Cys)	Pathogenic
4725936	NM_020661.4(AICDA):c.408dup (p.Ala137fs)	Pathogenic
4732297	NM_020661.4(AICDA):c.342C>A (p.Tyr114Ter)	Pathogenic
5122	NM_020661.4(AICDA):c.70C>T (p.Arg24Trp)	Pathogenic
5123	NM_020661.4(AICDA):c.203G>A (p.Trp68Ter)	Pathogenic
5125	NM_020661.4(AICDA):c.317T>C (p.Leu106Pro)	Pathogenic
5126	NM_020661.4(AICDA):c.415A>G (p.Met139Val)	Pathogenic
5127	NM_020661.4(AICDA):c.441C>A (p.Cys147Ter)	Pathogenic
5128	NM_020661.4(AICDA):c.452T>C (p.Phe151Ser)	Pathogenic
5129	NM_020661.4(AICDA):c.22_40del (p.Arg8fs)	Pathogenic
5130	NM_020661.4(AICDA):c.177_185del (p.Leu59_Leu62delinsPhe)	Pathogenic
617969	NM_020661.4(AICDA):c.259T>C (p.Cys87Arg)	Pathogenic
636339	NM_020661.4(AICDA):c.416T>C (p.Met139Thr)	Pathogenic
657907	NC_000012.12:g.(?8604264)(8612787_?)del	Pathogenic
950412	NM_020661.4(AICDA):c.338T>C (p.Leu113Pro)	Pathogenic
1473761	NM_020661.4(AICDA):c.544-2A>G	Likely pathogenic
1683705	NM_020661.4(AICDA):c.45C>G (p.Phe15Leu)	Likely pathogenic
1931360	NM_020661.4(AICDA):c.427+1G>A	Likely pathogenic
2137296	NM_020661.4(AICDA):c.293T>G (p.Leu98Arg)	Likely pathogenic
2833047	NM_020661.4(AICDA):c.8+1G>C	Likely pathogenic
3366472	NM_020661.4(AICDA):c.332C>A (p.Ala111Glu)	Likely pathogenic
3382113	NM_020661.4(AICDA):c.22del (p.Arg8fs)	Likely pathogenic
3658161	NM_020661.4(AICDA):c.4_8+3del	Likely pathogenic
374429	NM_020661.4(AICDA):c.92A>G (p.Tyr31Cys)	Likely pathogenic
4798412	NM_020661.4(AICDA):c.427+2T>C	Likely pathogenic
802819	NM_020661.4(AICDA):c.417G>T (p.Met139Ile)	Likely pathogenic

SpliceAI

456 predictions. Top by Δscore:

Variant	Effect	Δscore
12:8604338:C:CC	acceptor_gain	1.0000
12:8606860:GATAC:G	donor_loss	1.0000
12:8606863:ACCTT:A	donor_loss	1.0000
12:8606864:CC:C	donor_loss	1.0000
12:8607008:AGAGG:A	acceptor_gain	1.0000
12:8607009:GAGG:G	acceptor_gain	1.0000
12:8607010:AGG:A	acceptor_gain	1.0000
12:8607011:GG:G	acceptor_gain	1.0000
12:8607012:GCTGT:G	acceptor_loss	1.0000
12:8607013:C:CA	acceptor_loss	1.0000
12:8607013:C:CC	acceptor_gain	1.0000
12:8607019:G:GC	acceptor_gain	1.0000
12:8604334:GGGG:G	acceptor_gain	0.9900
12:8605279:AG:A	donor_gain	0.9900
12:8605481:CCGTT:C	acceptor_gain	0.9900
12:8605482:CGTT:C	acceptor_gain	0.9900
12:8605482:CGTTC:C	acceptor_gain	0.9900
12:8605483:GTTCT:G	acceptor_loss	0.9900
12:8605484:TT:T	acceptor_gain	0.9900
12:8605484:TTC:T	acceptor_loss	0.9900
12:8605485:TCTGG:T	acceptor_loss	0.9900
12:8605486:C:CC	acceptor_gain	0.9900
12:8605486:C:G	acceptor_loss	0.9900
12:8605487:T:G	acceptor_loss	0.9900
12:8607015:G:C	acceptor_gain	0.9900
12:8607019:G:C	acceptor_gain	0.9900
12:8604334:GGGGC:G	acceptor_loss	0.9800
12:8604335:GGGC:G	acceptor_loss	0.9800
12:8604336:GG:G	acceptor_gain	0.9800
12:8604337:GC:G	acceptor_loss	0.9800

AlphaMissense

1293 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:8605387:G:C	S85R	0.999
12:8605387:G:T	S85R	0.999
12:8605389:T:G	S85R	0.999
12:8604897:A:C	F151L	0.998
12:8604897:A:T	F151L	0.998
12:8604899:A:G	F151L	0.998
12:8605404:A:G	W80R	0.998
12:8605404:A:T	W80R	0.998
12:8605392:A:G	W84R	0.997
12:8605392:A:T	W84R	0.997
12:8605394:G:A	S83F	0.997
12:8605399:G:C	F81L	0.997
12:8605399:G:T	F81L	0.997
12:8605400:A:G	F81S	0.997
12:8605401:A:G	F81L	0.997
12:8606976:G:C	F15L	0.997
12:8606976:G:T	F15L	0.997
12:8606978:A:G	F15L	0.997
12:8606988:A:C	F11L	0.997
12:8606988:A:T	F11L	0.997
12:8606989:A:G	F11S	0.997
12:8606990:A:G	F11L	0.997
12:8604909:G:C	C147W	0.996
12:8605225:C:A	M139I	0.996
12:8605225:C:G	M139I	0.996
12:8605225:C:T	M139I	0.996
12:8605409:A:T	V78D	0.996
12:8606970:A:C	N17K	0.996
12:8606970:A:T	N17K	0.996
12:8604910:C:T	C147Y	0.995

dbSNP variants (sampled 300 via entrez): RS1000061430 (12:8607345 C>T), RS1001118530 (12:8610291 G>A), RS1001179999 (12:8607710 G>A), RS1001398772 (12:8608018 G>A,C), RS1001483076 (12:8605671 A>G), RS1001952963 (12:8610595 A>G), RS1002190634 (12:8606000 C>G), RS1002303191 (12:8612934 G>T), RS1002806819 (12:8611003 G>A,T), RS1002848285 (12:8608857 G>C), RS1003003617 (12:8602177 C>T), RS1003472833 (12:8613598 A>G), RS1003850608 (12:8613976 A>G), RS1003887668 (12:8607947 C>T), RS1004027383 (12:8612205 A>G)

Disease associations

OMIM: gene MIM:605257 | disease phenotypes: MIM:605258

GenCC curated gene-disease

Disease	Classification	Inheritance
hyper-IgM syndrome type 2	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hyper-IgM syndrome type 2	Definitive	AR
hyper-IgM syndrome type 2	Definitive	AD

Mondo (1): hyper-IgM syndrome type 2 (MONDO:0011528)

Orphanet (1): Hyper-IgM syndrome type 2 (Orphanet:101089)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002205	Recurrent respiratory infections
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency
HP:0002959	Impaired Ig class switch recombination
HP:0003496	Increased circulating IgM level
HP:0004315	Decreased circulating IgG concentration
HP:0004798	Recurrent infection of the gastrointestinal tract
HP:0011463	Childhood onset
HP:0200117	Recurrent upper and lower respiratory tract infections
HP:0410295	Complete or near-complete absence of specific antibody response to tetanus vaccine

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006575_21	Takayasu arteritis	1.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067454 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
propylene dichloride	affects expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
SN50 peptide	decreases reaction, increases expression	1
Imatinib Mesylate	decreases expression, increases reaction	1
Arsenic Trioxide	decreases expression, increases reaction	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Dimethyl Sulfoxide	affects expression	1
Estradiol	affects binding, increases reaction, decreases reaction	1
Silicon Dioxide	decreases expression	1
Tamoxifen	affects binding, decreases reaction, increases reaction	1
Zearalenone	increases expression	1
4,4’-Diisothiocyanostilbene-2,2’-Disulfonic Acid	decreases activity, increases activity, increases response to substance	1
Antirheumatic Agents	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5636816	Binding	Induction of GFP-tagged AID degradation in human A549 cells at 20 uM	Development of chalcone-like derivatives and their biological and mechanistic investigations as novel influenza nuclear export inhibitors. — Eur J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.