AK2

Summary

AK2 (adenylate kinase 2, HGNC:362) is a protein-coding gene on chromosome 1p35.1, encoding Adenylate kinase 2, mitochondrial (P54819). Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. It is a selective cancer dependency (DepMap: 13.5% of cell lines).

Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2. Expression of these isozymes is tissue-specific and developmentally regulated. Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis. Mutations in this gene are the cause of reticular dysgenesis. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 1 and 2.

Source: NCBI Gene 204 — RefSeq curated summary.

At a glance

• Gene–disease (curated): reticular dysgenesis (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 267 total — 20 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 13.5% of screened cell lines
• MANE Select transcript: NM_001625

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:362
Approved symbol	AK2
Name	adenylate kinase 2
Location	1p35.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000004455
Ensembl biotype	protein_coding
OMIM	103020
Entrez	204

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 10 protein_coding, 8 retained_intron, 7 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000354858, ENST00000373449, ENST00000466029, ENST00000467905, ENST00000469238, ENST00000480134, ENST00000487289, ENST00000491241, ENST00000548033, ENST00000548559, ENST00000550338, ENST00000551979, ENST00000672308, ENST00000672715, ENST00000673291, ENST00000695598, ENST00000695599, ENST00000695600, ENST00000695601, ENST00000695602, ENST00000695603, ENST00000695604, ENST00000695605, ENST00000695606, ENST00000910011, ENST00000910012

RefSeq mRNA: 8 — MANE Select: NM_001625 NM_001199199, NM_001319139, NM_001319140, NM_001319141, NM_001319142, NM_001319143, NM_001625, NM_013411

CCDS: CCDS373, CCDS374, CCDS81294, CCDS81295, CCDS81296

Canonical transcript exons

ENST00000672715 — 6 exons

Exon	Start	End
ENSE00001727989	33036736	33036883
ENSE00003491798	33024442	33024567
ENSE00003500664	33021367	33021461
ENSE00003644106	33021593	33021703
ENSE00003667542	33014522	33014594
ENSE00003891667	33007986	33013402

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 98.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.1564 / max 228.4067, expressed in 1823 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11600	28.7441	1823
11603	1.1081	356
11601	0.2848	108
11599	0.0194	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	98.11	gold quality
mucosa of transverse colon	UBERON:0004991	98.10	gold quality
metanephros cortex	UBERON:0010533	97.79	gold quality
colonic epithelium	UBERON:0000397	97.63	gold quality
gastrocnemius	UBERON:0001388	97.58	gold quality
right atrium auricular region	UBERON:0006631	97.53	gold quality
left lobe of thyroid gland	UBERON:0001120	97.51	gold quality
right lobe of thyroid gland	UBERON:0001119	97.37	gold quality
muscle of leg	UBERON:0001383	97.32	gold quality
right lobe of liver	UBERON:0001114	97.27	gold quality
apex of heart	UBERON:0002098	97.21	gold quality
left adrenal gland cortex	UBERON:0035825	97.17	gold quality
left adrenal gland	UBERON:0001234	97.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.09	gold quality
minor salivary gland	UBERON:0001830	97.08	gold quality
lower esophagus mucosa	UBERON:0035834	97.07	gold quality
right adrenal gland	UBERON:0001233	97.03	gold quality
transverse colon	UBERON:0001157	96.98	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.98	gold quality
right adrenal gland cortex	UBERON:0035827	96.87	gold quality
monocyte	CL:0000576	96.75	gold quality
body of pancreas	UBERON:0001150	96.75	gold quality
body of stomach	UBERON:0001161	96.74	gold quality
mononuclear cell	CL:0000842	96.71	gold quality
esophagus mucosa	UBERON:0002469	96.69	gold quality
endocervix	UBERON:0000458	96.65	gold quality
islet of Langerhans	UBERON:0000006	96.63	gold quality
leukocyte	CL:0000738	96.60	gold quality
ectocervix	UBERON:0012249	96.54	gold quality
ventricular zone	UBERON:0003053	96.51	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	5.50
E-MTAB-3929	no	481.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting AK2, 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-8485	100.00	77.57	4731
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-1283	99.69	72.42	3009

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• These results suggest that, acting in concert with FADD and caspase-10, AK2 mediates a novel intrinsic apoptotic pathway that may be involved in tumorigenesis. (PMID:17952061)
• The alpha-borano or alpha-H on PMEA and PMPA were detrimental to the activity of recombinant human AMP kinases 2 (PMID:18404568)
• Biallelic mutations in AK2 (adenylate kinase 2) in seven individuals affected with reticular dysgenesis and sensorineural deafness, were identified. (PMID:19043416)
• The gene encoding the mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2) is mutated in individuals with reticular dysgenesis. (PMID:19043417)
• results suggest that AK2 is an associated activator of DUSP26 and suppresses cell proliferation by FADD dephosphorylation, postulating AK2 as a negative regulator of tumour growth. (PMID:24548998)
• AK2 is indispensable for neutrophil differentiation, indicating a possible causative link between AK2 deficiency and neutropenia in reticular dysgenesis. (PMID:24587121)
• AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages. (PMID:26270350)
• In conclusion, our data suggest that SIRPalpha signaling through SHP-2-PI3K-Akt2 strongly influences osteoblast differentiation from bone marrow stromal cells. (PMID:27422603)
• Reticular dysgenesis -patient derived induced pluripotent stem cells can recapitulate disease phenotype which can be rescued by AK2 overexpression. (PMID:29462620)
• Genetic variants of AK2 activates tenofovir for HIV therapy. (PMID:29641561)
• Methylation on AK2 is associated with the development of anti-tuberculosis drug-induced liver injury. (PMID:31247120)
• Prognostic and therapeutic potential of Adenylate kinase 2 in lung adenocarcinoma. (PMID:31780678)
• Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation. (PMID:31862378)
• Reticular dysgenesis caused by an intronic pathogenic variant in AK2. (PMID:32532877)
• Adenylate kinase 2 expression and addiction in T-ALL. (PMID:33560378)
• AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis. (PMID:35585049)
• Adenylate kinase 2 is a biomarker related to the prognosis of glioma and the immune microenvironment. (PMID:37161605)
• Colorectal cancer-associated mutations impair EphB1 kinase function. (PMID:37527777)
• NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome. (PMID:38598835)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ak2	ENSDARG00000005926
mus_musculus	Ak2	ENSMUSG00000028792
rattus_norvegicus	Ak2	ENSRNOG00000000122
drosophila_melanogaster	Ak2	FBGN0283494
caenorhabditis_elegans		WBGENE00002879

Paralogs (9): AK1 (ENSG00000106992), AK7 (ENSG00000140057), AK3 (ENSG00000147853), AK5 (ENSG00000154027), AK9 (ENSG00000155085), CMPK1 (ENSG00000162368), AK4 (ENSG00000162433), AK8 (ENSG00000165695), AK4P3 (ENSG00000233381)

Protein

Protein identifiers

Adenylate kinase 2, mitochondrial — P54819 (reviewed: P54819)

Alternative names: ATP-AMP transphosphorylase 2, ATP:AMP phosphotransferase, Adenylate monophosphate kinase

All UniProt accessions (10): P54819, A0A140VK93, A0A5F9ZHP2, A0A5K1VW67, A0A8Q3SHW4, F8VPP1, F8VY04, F8VZG5, F8W1A4, G3V213

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Adenylate kinase activity is critical for regulation of the phosphate utilization and the AMP de novo biosynthesis pathways. Plays a key role in hematopoiesis.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion intermembrane space.

Tissue specificity. Present in most tissues. Present at high level in heart, liver and kidney, and at low level in brain, skeletal muscle and skin. Present in thrombocytes but not in erythrocytes, which lack mitochondria. Present in all nucleated cell populations from blood, while AK1 is mostly absent. In spleen and lymph nodes, mononuclear cells lack AK1, whereas AK2 is readily detectable. These results indicate that leukocytes may be susceptible to defects caused by the lack of AK2, as they do not express AK1 in sufficient amounts to compensate for the AK2 functional deficits (at protein level).

Disease relevance. Reticular dysgenesis (RDYS) [MIM:267500] A fatal form of severe combined immunodeficiency, characterized by absence of granulocytes, almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immunity, leading to fatal septicemia within days after birth. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Consists of three domains, a large central CORE domain and two small peripheral domains, NMPbind and LID, which undergo movements during catalysis. The LID domain closes over the site of phosphoryl transfer upon ATP binding. Assembling and disassembling the active center during each catalytic cycle provides an effective means to prevent ATP hydrolysis.

Similarity. Belongs to the adenylate kinase family. AK2 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
P54819-1	1, AK2A, AK2isoA	yes
P54819-2	2, AK2B, AK2isoB
P54819-3	3, AK2C
P54819-4	4, AK2D
P54819-5	5
P54819-6	6

RefSeq proteins (8): NP_001186128, NP_001306068, NP_001306069, NP_001306070, NP_001306071, NP_001306072, NP_001616, NP_037543 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000850	Adenylat/UMP-CMP_kin	Family
IPR006259	Adenyl_kin_sub	Family
IPR007862	Adenylate_kinase_lid-dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR028587	AK2	Family
IPR033690	Adenylat_kinase_CS	Conserved_site

Pfam: PF00406, PF05191

Enzyme classification (BRENDA):

• EC 2.7.4.3 — adenylate kinase (BRENDA: 73 organisms, 259 substrates, 134 inhibitors, 192 Km, 47 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
AMP	0.0014–1.9	59
ATP	0.0001–7	58
ADP	0.003–16.8	27
2 ADP	0.006–0.15	5
DAMP	0.507–2	2
2’-DAMP	0.85	1
7-DEAZAADENOSINE 5’-MONOPHOSPHATE	0.73	1
ADP3-	0.03	1
CMP	0.0002	1

Catalyzed reactions (Rhea), 1 shown:

• AMP + ATP = 2 ADP (RHEA:12973)

UniProt features (55 total): binding site 12, helix 9, modified residue 8, strand 7, splice variant 6, region of interest 3, sequence variant 3, chain 2, turn 2, initiator methionine 1, disulfide bond 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2C9Y	X-RAY DIFFRACTION	2.1
9GR0	ELECTRON MICROSCOPY	2.61
9FL7	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54819-F1	90.49	0.83

Functional residue map

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

Ligand- & substrate-binding residues (12): 72–74; 100–103; 107; 138; 142; 151–152; 175; 186; 214; 25–30; 46; 51

Post-translational modifications (8): 1, 4, 58, 62, 93, 133, 181, 195

Disulfide bonds (1): 42–92

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides

MSigDB gene sets: 0 (showing top):

GO Biological Process (8): ADP biosynthetic process (GO:0006172), nucleobase-containing small molecule interconversion (GO:0015949), AMP metabolic process (GO:0046033), ATP metabolic process (GO:0046034), nucleobase-containing compound metabolic process (GO:0006139), nucleotide metabolic process (GO:0009117), nucleoside monophosphate metabolic process (GO:0009123), nucleoside monophosphate phosphorylation (GO:0046940)

GO Molecular Function (9): AMP kinase activity (GO:0004017), ATP binding (GO:0005524), nucleotide binding (GO:0000166), nucleoside diphosphate kinase activity (GO:0004550), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, phosphate group as acceptor (GO:0016776), nucleobase-containing compound kinase activity (GO:0019205)

GO Cellular Component (7): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), extracellular exosome (GO:0070062), sperm mitochondrial sheath (GO:0097226), mitochondrial matrix (GO:0005759), sperm flagellum (GO:0036126)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of nucleotides	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
purine ribonucleotide metabolic process	2
nucleoside phosphate metabolic process	2
transferase activity, transferring phosphorus-containing groups	2
cellular anatomical structure	2
purine ribonucleotide biosynthetic process	1
purine ribonucleoside diphosphate biosynthetic process	1
ADP metabolic process	1
nucleobase-containing small molecule metabolic process	1
purine ribonucleoside monophosphate metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
primary metabolic process	1
nucleoside monophosphate metabolic process	1
nucleotide biosynthetic process	1
nucleoside monophosphate kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
phosphotransferase activity, phosphate group as acceptor	1
nucleobase-containing compound kinase activity	1
binding	1
catalytic activity	1
kinase activity	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial envelope	1
organelle envelope lumen	1
extracellular vesicle	1
sperm midpiece	1
mitochondrion	1
intracellular organelle lumen	1
9+2 motile cilium	1

Protein interactions and networks

STRING

3697 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AK2	PGM1	P36871	848
AK2	ENO1	P06733	826
AK2	CASP10	Q92851	749
AK2	FADD	Q13158	740
AK2	PGM2	Q96G03	730
AK2	FUCA1	P04066	727
AK2	NME4	O00746	706
AK2	DUSP26	Q9BV47	699
AK2	PGC	P20142	682
AK2	ENO3	P13929	676
AK2	DGUOK	P78532	652
AK2	PGD	P52209	647
AK2	NT5M	Q9NPB1	621
AK2	DUSP28	Q4G0W2	603
AK2	DTYMK	P23919	595

IntAct

117 interactions, top by confidence:

A	B	Type	Score
AIFM1	AK2	psi-mi:“MI:0914”(association)	0.570
	AK2	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	AK2	psi-mi:“MI:0915”(physical association)	0.560
AK2		psi-mi:“MI:0915”(physical association)	0.560
AK2	PECAM1	psi-mi:“MI:0915”(physical association)	0.560
AK2	PMP22	psi-mi:“MI:0915”(physical association)	0.560
AK2	PRKACA	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	AK2	psi-mi:“MI:0915”(physical association)	0.560
AK2	TGFBR2	psi-mi:“MI:0915”(physical association)	0.560
AK2	VIM	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	AK2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (208): AK2 (Affinity Capture-MS), AK2 (Affinity Capture-MS), ACAA2 (Co-fractionation), AFG3L2 (Co-fractionation), AK2 (Co-fractionation), AK2 (Co-fractionation), DUT (Co-fractionation), FSCN1 (Co-fractionation), GNB2L1 (Co-fractionation), MRPS7 (Co-fractionation), NME1-NME2 (Co-fractionation), NME2 (Co-fractionation), SIGMAR1 (Co-fractionation), TKT (Co-fractionation), TRAP1 (Co-fractionation)

ESM2 similar proteins: A0A3Q0KGQ7, A5FRW5, A8F4T2, A8PR17, A8XZJ0, A9BFZ7, A9FGE0, A9KED8, A9NBU5, B0X5E3, B2B0E2, B2CNY4, B2KEK1, B3MCQ5, B3NQ53, B4I2A8, B4J672, B4KLY1, B4LP08, B4MQT3, B4PAR6, B4QBH8, B6J1M3, B6J8H9, B6YVU5, C0R2Y9, C6A2Q1, P34346, P49982, P54819, Q09629, Q1L8L9, Q254P2, Q290A8, Q3Z960, Q3ZZQ3, Q5L5W0, Q5REI7, Q68W99, Q6G2Y6

Diamond homologs: A0A3Q0KGQ7, A0ALU7, A1CQR5, A1D3M8, A2QPN9, A3LV51, A4RD93, A4W7F8, A4XXP5, A5DC72, A5E598, A5IBQ3, A6RHI1, A6RPU0, A6ZYI0, A7E8H8, A7THY5, A7ZIN4, A7ZXD2, A8PAA1, A8PR17, A8XZJ0, B0D360, B0X5E3, B0XPW9, B1IZC0, B1LJN2, B1XFR1, B2B0E2, B2CNY4, B2U4S7, B2W0K4, B3LG61, B3MCQ5, B3NQ53, B4I2A8, B4J672, B4KLY1, B4LP08, B4MQT3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 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
MAP kinase activation	6	22.1×	5e-05
Interleukin-17 signaling	6	18.1×	1e-04
MyD88 cascade initiated on plasma membrane	7	17.0×	5e-05
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	7	15.9×	5e-05
MyD88 dependent cascade initiated on endosome	7	15.9×	5e-05
Toll Like Receptor 10 (TLR10) Cascade	6	15.4×	2e-04
Toll Like Receptor 5 (TLR5) Cascade	6	15.4×	2e-04
Toll Like Receptor 3 (TLR3) Cascade	6	13.8×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
JNK cascade	5	11.9×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	14
Uncertain significance	100
Likely benign	82
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1379433	NM_001625.4(AK2):c.597_599dup (p.Tyr200Ter)	Pathogenic
1436300	NM_001625.4(AK2):c.409C>T (p.Arg137Ter)	Pathogenic
1453536	NM_001625.4(AK2):c.84dup (p.Gly29fs)	Pathogenic
1455489	NC_000001.10:g.(?33490023)(33502429_?)del	Pathogenic
1457960	NC_000001.10:g.(?33473829)(33478866_?)del	Pathogenic
18250	NM_001625.4(AK2):c.636_*4953del (p.Ser213fs)	Pathogenic
18251	NM_001625.4(AK2):c.118del (p.Cys40fs)	Pathogenic
18252	NM_001625.4(AK2):c.1A>G (p.Met1Val)	Pathogenic
18253	NM_001625.4(AK2):c.331-1G>A	Pathogenic
18254	NM_001625.4(AK2):c.453del (p.Tyr152fs)	Pathogenic
18256	NM_001625.4(AK2):c.494A>G (p.Asp165Gly)	Pathogenic
18259	NG_016269.1:g.(5157_17324)_(17451_20188)del	Pathogenic
18261	NM_001625.4(AK2):c.697A>T (p.Lys233Ter)	Pathogenic
18262	NM_001625.4(AK2):c.25G>T (p.Glu9Ter)	Pathogenic
2124398	NM_001625.4(AK2):c.374_375del (p.Val125fs)	Pathogenic
3062788	GRCh37/hg19 1p35.1(chr1:33490421-33599915)x1	Pathogenic
3247681	NC_000001.10:g.(?33480103)(33480215_?)del	Pathogenic
3583653	NM_001625.4(AK2):c.3G>A (p.Met1Ile)	Pathogenic
446366	NM_001625.4(AK2):c.523del (p.Arg175fs)	Pathogenic
661953	NM_001625.4(AK2):c.330+5G>A	Pathogenic
1027587	NM_001625.4(AK2):c.523C>G (p.Arg175Gly)	Likely pathogenic
1027623	NM_001625.4(AK2):c.330+1G>C	Likely pathogenic
1067803	NM_001625.4(AK2):c.614_615del (p.Gly205fs)	Likely pathogenic
1301340	NM_001625.4(AK2):c.600C>G (p.Tyr200Ter)	Likely pathogenic
1339680	NM_001625.4(AK2):c.498_499dup (p.Ile167fs)	Likely pathogenic
1339681	NM_001625.4(AK2):c.499-1_499insATGAC (p.Ile167fs)	Likely pathogenic
18258	NM_001625.4(AK2):c.556C>T (p.Arg186Cys)	Likely pathogenic
3583643	NM_001625.4(AK2):c.400_401del (p.Leu134fs)	Likely pathogenic
3724971	NM_001625.4(AK2):c.425+1G>T	Likely pathogenic
4292743	NM_001625.4(AK2):c.523C>T (p.Arg175Ter)	Likely pathogenic

SpliceAI

1142 predictions. Top by Δscore:

Variant	Effect	Δscore
1:33014506:T:TA	donor_gain	1.0000
1:33014518:ATAC:A	donor_loss	1.0000
1:33014520:A:AC	donor_gain	1.0000
1:33014520:A:C	donor_loss	1.0000
1:33014520:ACGT:A	donor_gain	1.0000
1:33014521:C:CC	donor_gain	1.0000
1:33014521:CGT:C	donor_gain	1.0000
1:33014521:CGTC:C	donor_gain	1.0000
1:33014521:CGTCA:C	donor_gain	1.0000
1:33014523:T:TA	donor_gain	1.0000
1:33014590:TCAGC:T	acceptor_gain	1.0000
1:33014591:CAGC:C	acceptor_gain	1.0000
1:33014591:CAGCC:C	acceptor_gain	1.0000
1:33014592:AGC:A	acceptor_gain	1.0000
1:33014593:GC:G	acceptor_gain	1.0000
1:33014593:GCCT:G	acceptor_loss	1.0000
1:33014594:CC:C	acceptor_gain	1.0000
1:33014595:C:CC	acceptor_gain	1.0000
1:33021363:ATAC:A	donor_loss	1.0000
1:33021364:TACCT:T	donor_loss	1.0000
1:33021365:ACC:A	donor_loss	1.0000
1:33021365:ACCTT:A	donor_gain	1.0000
1:33021366:C:CT	donor_loss	1.0000
1:33021366:CCTTC:C	donor_gain	1.0000
1:33021369:T:TA	donor_gain	1.0000
1:33021458:CGAG:C	acceptor_gain	1.0000
1:33024568:C:CA	acceptor_loss	1.0000
1:33013402:TC:T	acceptor_loss	0.9900
1:33013403:C:CC	acceptor_gain	0.9900
1:33013404:T:G	acceptor_loss	0.9900

AlphaMissense

1568 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:33013369:C:G	D178H	1.000
1:33013368:T:A	D178V	0.999
1:33013368:T:G	D178A	0.999
1:33013372:C:G	D177H	0.999
1:33021367:C:A	R142M	0.999
1:33021602:C:A	Q107H	0.999
1:33021602:C:G	Q107H	0.999
1:33021618:G:T	P102H	0.999
1:33021619:G:A	P102S	0.999
1:33021620:G:C	F101L	0.999
1:33021620:G:T	F101L	0.999
1:33021622:A:G	F101L	0.999
1:33021625:C:G	G100R	0.999
1:33024508:C:A	R51S	0.999
1:33024508:C:G	R51S	0.999
1:33024509:C:A	R51M	0.999
1:33024509:C:G	R51T	0.999
1:33024521:C:T	G47E	0.999
1:33024522:C:A	G47W	0.999
1:33024522:C:G	G47R	0.999
1:33024522:C:T	G47R	0.999
1:33036745:T:A	K28N	0.999
1:33036745:T:G	K28N	0.999
1:33036746:T:A	K28I	0.999
1:33036747:T:G	K28Q	0.999
1:33036749:C:T	G27D	0.999
1:33036764:C:T	G22E	0.999
1:33036765:C:G	G22R	0.999
1:33036765:C:T	G22R	0.999
1:33013341:A:G	L187P	0.998

dbSNP variants (sampled 300 via entrez): RS1000109857 (1:33023723 T>C), RS1000275463 (1:33015005 T>A), RS1000538619 (1:33034670 T>C), RS1000555809 (1:33008729 G>C), RS1000645415 (1:33013369 C>T), RS1000726225 (1:33019805 G>C), RS1000897128 (1:33026488 A>C,G), RS1000927768 (1:33026269 G>A), RS1001097005 (1:33032080 A>C,G), RS1001111290 (1:33021821 T>C), RS1001276666 (1:33016362 C>A,T), RS1001389437 (1:33015483 T>A,C), RS1001393105 (1:33023206 T>C), RS1001466226 (1:33032274 T>C), RS1001565091 (1:33028976 G>A)

Disease associations

OMIM: gene MIM:103020 | disease phenotypes: MIM:267500

GenCC curated gene-disease

Disease	Classification	Inheritance
reticular dysgenesis	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
reticular dysgenesis	Definitive	AR

Mondo (2): reticular dysgenesis (MONDO:0009973), severe combined immunodeficiency (MONDO:0015974)

Orphanet (2): Reticular dysgenesis (Orphanet:33355), Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000778	Hypoplasia of the thymus
HP:0000988	Skin rash
HP:0001508	Failure to thrive
HP:0001824	Weight loss
HP:0001874	Abnormality of neutrophils
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0001944	Dehydration
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002205	Recurrent respiratory infections
HP:0003287	Abnormality of mitochondrial metabolism
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004430	Severe combined immunodeficiency
HP:0005354	Absent cellular immunity
HP:0005374	Cellular immunodeficiency
HP:0005387	Combined immunodeficiency
HP:0005541	Congenital agranulocytosis
HP:0010515	Aplasia/Hypoplasia of the thymus
HP:0011840	Abnormal T cell physiology
HP:0100806	Sepsis
HP:0200042	Skin ulcer

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003876_2	Gut microbiota (beta diversity)	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C538361	Reticular dysgenesis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4938 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,156 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL598797	CUDC-101	1	2,156

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.25	Kd	56.75	nM	CHEMBL5653589
7.25	ED50	56.75	nM	CHEMBL5653589
5.99	Kd	1036	nM	CUDC-101

PubChem BioAssay actives

2 with measured affinity, of 264 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147829: Binding affinity to human AK2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0568	uM
7-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyheptanamide	1424909: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.0360	uM

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
bisphenol A	decreases expression, increases expression, affects cotreatment, affects expression, increases abundance	3
trichostatin A	affects cotreatment, increases expression	2
sodium arsenite	decreases expression, increases expression	2
ochratoxin A	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Nickel	increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance, decreases expression	1
methylmercuric chloride	decreases expression	1
arsenite	affects binding, increases reaction	1
afimoxifene	decreases response to substance	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
diallyl trisulfide	increases expression	1
CD 437	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Irinotecan	increases response to substance	1
Resveratrol	affects cotreatment, increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3378152	Binding	Activity of recombinant AK2 (unknown origin) assessed as ADP formation by spectroscopic pyruvate kinase/lactate dehydrogenase coupled assay	Synthesis of {[5-(adenin-9-yl)-2-furyl]methoxy}methyl phosphonic acid and evaluations against human adenylate kinases. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2RB	Abcam HEK293T AK2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID
NCT04246840	Not specified	COMPLETED	Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft
NCT04331483	Not specified	WITHDRAWN	A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts