Adenosine kinase deficiency

Summary

Adenosine kinase deficiency (MONDO:0100255) is a disease caused by ADK (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ADK (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 53

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	adenosine kinase deficiency
Mondo ID	MONDO:0100255
MeSH	C567015
OMIM	611094, 614300
Orphanet	289290
DOID	DOID:0111038
UMLS	C4706555
MedGen	1632232
GARD	0017321
Is cancer (heuristic)	no

Also known as: adenosine kinase deficiency · ADK deficiency · ADK hypermethioninemia · autosomal recessive intellectual disability 8 · hypermethioninemia due to adenosine kinase deficiency · hypermethioninemia encephalopathy due to adenosine kinase deficiency · hypermethioninemia encephalopathy due to ADK deficiency · mental retardation, autosomal recessive 8 · mental retardation, autosomal recessive 8, formerly · mental retardation, autosomal recessive 8; MRT8 · MRT8

Data availability: 53 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › disorder of methionine catabolism › adenosine kinase deficiency

Related subtypes (2): glycine N-methyltransferase deficiency, hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

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

53 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 7 benign, 6 likely pathogenic, 5 likely benign, 4 conflicting classifications of pathogenicity, 4 pathogenic, 3 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29603	NM_006721.4(ADK):c.953C>A (p.Ala318Glu)	ADK	Pathogenic	criteria provided, single submitter
29604	NM_006721.4(ADK):c.704A>C (p.Asp235Ala)	ADK	Pathogenic	no assertion criteria provided
29605	NM_006721.4(ADK):c.89G>A (p.Gly30Glu)	ADK	Pathogenic	no assertion criteria provided
3775248	NM_006721.4(ADK):c.647_651del (p.Ala216fs)	ADK	Pathogenic	criteria provided, single submitter
802589	NM_006721.4(ADK):c.1031C>T (p.Ala344Val)	ADK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584480	NM_006721.4(ADK):c.642_645del (p.Ser215fs)	ADK	Likely pathogenic	criteria provided, single submitter
2584481	NM_006721.4(ADK):c.916C>T (p.Gln306Ter)	ADK	Likely pathogenic	criteria provided, single submitter
3597273	NM_006721.4(ADK):c.-10_4del (p.Met1fs)	ADK	Likely pathogenic	criteria provided, single submitter
3597287	NM_006721.4(ADK):c.569_570del (p.Thr190fs)	ADK	Likely pathogenic	criteria provided, single submitter
4845594	NM_006721.4(ADK):c.64A>T (p.Arg22Ter)	ADK	Likely pathogenic	criteria provided, single submitter
800875	NM_006721.4(ADK):c.813dup (p.Asn272fs)	ADK	Likely pathogenic	no assertion criteria provided
191003	NM_006721.4(ADK):c.741T>A (p.Phe247Leu)	ADK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3597279	NM_006721.4(ADK):c.2T>C (p.Met1Thr)	ADK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4689182	NM_006721.4(ADK):c.2T>A (p.Met1Lys)	ADK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877826	NM_006721.4(ADK):c.429C>T (p.Cys143=)	ADK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2444120	NM_006721.4(ADK):c.374T>C (p.Val125Ala)	ADK	Uncertain significance	criteria provided, single submitter
300830	NM_006721.4(ADK):c.66-24151A>T	ADK	Uncertain significance	criteria provided, single submitter
300832	NM_006721.4(ADK):c.66-24083G>C	ADK	Uncertain significance	criteria provided, single submitter
300833	NM_006721.4(ADK):c.66-24009G>T	ADK	Uncertain significance	criteria provided, single submitter
300834	NM_006721.4(ADK):c.66-23966T>C	ADK	Uncertain significance	criteria provided, single submitter
300836	NM_006721.4(ADK):c.220A>G (p.Lys74Glu)	ADK	Uncertain significance	criteria provided, multiple submitters, no conflicts
300837	NM_006721.4(ADK):c.259A>G (p.Ile87Val)	ADK	Uncertain significance	criteria provided, multiple submitters, no conflicts
300838	NM_006721.4(ADK):c.441C>T (p.Asp147=)	ADK	Uncertain significance	criteria provided, single submitter
300842	NM_006721.4(ADK):c.763-9T>C	ADK	Uncertain significance	criteria provided, single submitter
300844	NM_006721.4(ADK):c.*157G>A	ADK	Uncertain significance	criteria provided, single submitter
300845	NM_006721.4(ADK):c.*337T>G	ADK	Uncertain significance	criteria provided, single submitter
3376384	NM_006721.4(ADK):c.79T>C (p.Phe27Leu)	ADK	Uncertain significance	criteria provided, single submitter
3597283	NM_006721.4(ADK):c.66-23876T>A	ADK	Uncertain significance	criteria provided, single submitter
4814116	NM_006721.4(ADK):c.313G>A (p.Gly105Arg)	ADK	Uncertain significance	criteria provided, single submitter
877827	NM_006721.4(ADK):c.494A>C (p.Lys165Thr)	ADK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
ADK	Strong	Autosomal recessive	adenosine kinase deficiency	4
AK1	Strong	Autosomal recessive	adenosine kinase deficiency	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADK	Orphanet:289290	Hypermethioninemia encephalopathy due to adenosine kinase deficiency
AK1	Orphanet:86817	Hemolytic anemia due to adenylate kinase deficiency

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
ADK	HGNC:257	ENSG00000156110	P55263	Adenosine kinase	gencc,clinvar
AK1	HGNC:361	ENSG00000106992	P00568	Adenylate kinase isoenzyme 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADK	Adenosine kinase	Adenosine kinase that mediates the phosphorylation of the purine nucleoside adenosine at the 5’ position in an ATP-dependent manner: catalyzes phosphorylation of both unmodified and modified adenosines.
AK1	Adenylate kinase isoenzyme 1	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	2	27.7×	0.001

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADK	Kinase	yes	2.7.1.20	Adenokinase, Carboh/pur_kinase_PfkB_CS, PfkB_dom
AK1	Kinase	yes	2.7.4.3	Adenylat/UMP-CMP_kin, AK1/5, P-loop_NTPase

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
cartilage tissue	1
liver	1
tongue squamous epithelium	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADK	290	ubiquitous	marker	cartilage tissue, tongue squamous epithelium, liver
AK1	144	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AK1	3,526
ADK	3,028

Intra-cohort edges

A	B	Sources
ADK	AK1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADK	P55263	7
AK1	P00568	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of nucleotides	2	300.5×	8e-05	ADK, AK1
Nucleotide salvage	1	571.0×	0.004	ADK
Ribavirin ADME	1	519.1×	0.004	ADK
Purine salvage	1	439.2×	0.004	ADK
Interconversion of nucleotide di- and triphosphates	1	178.4×	0.008	AK1
Metabolism	2	11.6×	0.009	ADK, AK1
Drug ADME	1	114.2×	0.009	ADK

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
dATP biosynthetic process	1	8426.0×	0.001	ADK
dAMP salvage	1	2808.7×	0.001	ADK
ribonucleoside monophosphate biosynthetic process	1	2106.5×	0.001	ADK
GMP salvage	1	1404.3×	0.001	ADK
AMP salvage	1	1404.3×	0.001	ADK
purine nucleobase metabolic process	1	1203.7×	0.001	ADK
purine ribonucleoside salvage	1	1203.7×	0.001	ADK
ADP biosynthetic process	1	1203.7×	0.001	AK1
nucleoside triphosphate biosynthetic process	1	1053.2×	0.001	AK1
AMP metabolic process	1	936.2×	0.001	AK1
nucleobase-containing small molecule interconversion	1	842.6×	0.001	AK1
ATP metabolic process	1	234.1×	0.004	AK1

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
ADK	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADK	6	4
AK1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AFATINIB	4	ADK
ALVOCIDIB	3	ADK
ADAVOSERTIB	2	ADK
SAPITINIB	2	ADK
BI-2536	2	ADK
GSK-461364	1	ADK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ADK	169	Binding:106, ADMET:57, Functional:6
AK1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADK	2.7.1.20	adenosine kinase
AK1	2.7.4.3	adenylate kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ADK	169

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

6 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)
AFATINIB	4	ADK
ALVOCIDIB	3	ADK
ADAVOSERTIB	2	ADK
SAPITINIB	2	ADK
BI-2536	2	ADK
GSK-461364	1	ADK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ADK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AK1
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)
AK1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.