AK5

Chr 1

adenylate kinase 5

Also known as: AK6

NCBI Gene: 26289ENSG00000154027UniProt: Q9Y6K8

The protein functions as a nucleoside monophosphate kinase that catalyzes phosphate transfer between nucleoside triphosphates and monophosphates, maintaining cellular adenine nucleotide balance and is expressed exclusively in the brain. Mutations cause autosomal recessive intellectual disability with seizures and spasticity. The gene is highly constrained against loss-of-function variants (LOEUF 0.558), reflecting its essential role in brain metabolism.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
14
Pubs (1 yr)
17
P/LP submissions
0%
P/LP missense
0.56
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— AK5
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
17 unique Pathogenic / Likely Pathogenic· 76 VUS of 111 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.56LOEUF
pLI 0.003
Z-score 3.43
OE 0.33 (0.20–0.56)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.15Z-score
OE missense 0.66 (0.59–0.74)
207 obs / 314.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.33 (0.20–0.56)
0≤0.351.4
Missense OE0.66 (0.59–0.74)
0≤0.61.4
Synonymous OE1.17
0≤1.21.6
LoF obs/exp: 10 / 30.4Missense obs/exp: 207 / 314.2Syn Z: -1.43
DN
0.77top 25%
GOF
0.7127th %ile
LOF
0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

111 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic2
VUS76
Likely Benign4
Benign4
15
Pathogenic
2
Likely Pathogenic
76
VUS
4
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
15
0
15
Likely Pathogenic
0
0
2
0
2
VUS
0
66
10
0
76
Likely Benign
0
1
1
2
4
Benign
0
0
4
0
4
Total067322101

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

AK5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients