Hemolytic anemia due to adenylate kinase deficiency

Summary

Hemolytic anemia due to adenylate kinase deficiency (MONDO:0012967) is a disease caused by AK1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AK1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 51

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hemolytic anemia due to adenylate kinase deficiency
Mondo ID	MONDO:0012967
MeSH	C567228
OMIM	612631
Orphanet	86817
DOID	DOID:0051004
SNOMED CT	766982000
UMLS	C2675459
MedGen	390802
GARD	0016760
Is cancer (heuristic)	no

Also known as: adenylate kinase deficiency, hemolytic anaemia due to · adenylate kinase deficiency, hemolytic anemia due to

Data availability: 51 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital nonspherocytic hemolytic anemia › hemolytic anemia due to adenylate kinase deficiency

Related subtypes (9): anemia, nonspherocytic hemolytic, gamma-glutamylcysteine synthetase deficiency, glutathione synthetase deficiency without 5-oxoprolinuria, non-spherocytic hemolytic anemia due to hexokinase deficiency, hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency, pyruvate kinase deficiency of red cells, hemolytic anemia due to glucophosphate isomerase deficiency, hemolytic anemia due to glutathione reductase deficiency, hemolytic anemia due to erythrocyte adenosine deaminase overproduction

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

51 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1162194	NM_000476.3(AK1):c.301C>A (p.Gln101Lys)	AK1	Pathogenic	criteria provided, single submitter
18263	NM_000476.3(AK1):c.382C>T (p.Arg128Trp)	AK1	Pathogenic	no assertion criteria provided
18265	NM_000476.3(AK1):c.491A>G (p.Tyr164Cys)	AK1	Pathogenic	no assertion criteria provided
18266	NM_000476.3(AK1):c.118G>A (p.Gly40Arg)	AK1	Pathogenic	no assertion criteria provided
18267	NM_000476.3(AK1):c.190G>A (p.Gly64Arg)	AK1	Pathogenic	no assertion criteria provided
18268	NM_000476.3(AK1):c.418GAC[1] (p.Asp141del)	AK1	Pathogenic	no assertion criteria provided
18269	NM_000476.3(AK1):c.139del (p.Val47fs)	ST6GALNAC4-ST6GALNAC6-AK1	Pathogenic	no assertion criteria provided
18264	NM_000476.3(AK1):c.319C>T (p.Arg107Ter)	AK1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081098	NM_000476.3(AK1):c.166A>T (p.Lys56Ter)	AK1	Likely pathogenic	criteria provided, single submitter
4081099	NM_000476.3(AK1):c.44-5_48delinsC	AK1	Likely pathogenic	criteria provided, single submitter
4541480	NM_000476.3(AK1):c.248A>G (p.Lys83Arg)	AK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1302035	NM_000476.3(AK1):c.85G>A (p.Val29Met)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2332217	NM_000476.3(AK1):c.409G>A (p.Gly137Arg)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2364263	NM_000476.3(AK1):c.55T>G (p.Ser19Ala)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438949	NM_000476.3(AK1):c.148_149delinsAA (p.Gly50Asn)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438950	NM_000476.3(AK1):c.535G>C (p.Val179Leu)	AK1	Uncertain significance	criteria provided, single submitter
2438951	NM_000476.3(AK1):c.229C>T (p.Arg77Trp)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438952	NM_000476.3(AK1):c.158G>A (p.Arg53Lys)	AK1	Uncertain significance	criteria provided, single submitter
2438953	NM_000476.3(AK1):c.78G>C (p.Glu26Asp)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438954	NM_000476.3(AK1):c.238A>G (p.Met80Val)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2690868	NM_000476.3(AK1):c.254A>G (p.Asn85Ser)	AK1	Uncertain significance	criteria provided, single submitter
2690869	NM_000476.3(AK1):c.530G>A (p.Gly177Asp)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3103330	NM_000476.3(AK1):c.506T>C (p.Ile169Thr)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3766572	NM_000476.3(AK1):c.482T>C (p.Ile161Thr)	AK1	Uncertain significance	criteria provided, single submitter
4077876	NM_000476.3(AK1):c.377C>A (p.Thr126Asn)	AK1	Uncertain significance	criteria provided, single submitter
4077877	NM_000476.3(AK1):c.292G>A (p.Glu98Lys)	AK1	Uncertain significance	criteria provided, single submitter
4077878	NM_000476.3(AK1):c.446G>A (p.Arg149Gln)	AK1	Uncertain significance	criteria provided, single submitter
4077880	NM_000476.3(AK1):c.230G>A (p.Arg77Gln)	AK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4077881	NM_000476.3(AK1):c.82A>G (p.Ile28Val)	AK1	Uncertain significance	criteria provided, single submitter
4077882	NM_000476.3(AK1):c.389T>C (p.Leu130Ser)	AK1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · 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
AK1	Strong	Autosomal recessive	adenosine kinase deficiency	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AK1	Orphanet:86817	Hemolytic anemia due to adenylate kinase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
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)
AK1	Adenylate kinase isoenzyme 1	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.

Protein-family classification

Druggable: 1 · 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	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AK1	144	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AK1	3,526

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AK1	P00568	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.005	AK1
Metabolism of nucleotides	1	300.5×	0.005	AK1
Metabolism	1	11.6×	0.086	AK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ADP biosynthetic process	1	2407.4×	7e-04	AK1
nucleoside triphosphate biosynthetic process	1	2106.5×	7e-04	AK1
AMP metabolic process	1	1872.4×	7e-04	AK1
nucleobase-containing small molecule interconversion	1	1685.2×	7e-04	AK1
ATP metabolic process	1	468.1×	0.002	AK1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AK1	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
AK1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AK1	2.7.4.3	adenylate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	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.