AK3

Chr 9

adenylate kinase 3

Also known as: AK3L1, AK6, AKL3L, AKL3L1, FIX

NCBI Gene: 50808 ENSG00000147853 UniProt: P27144 OMIM: 609290

The protein is a mitochondrial nucleoside phosphate kinase that maintains cellular nucleotide homeostasis by catalyzing phosphorylation reactions, particularly converting AMP to ADP using ATP or GTP as phosphate donors. Mutations cause autosomal recessive reticular dysgenesis, a severe combined immunodeficiency with sensorineural hearing loss that presents in early infancy. The gene shows very low constraint against loss-of-function variants (pLI 0.0001), consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a GTP:ATP phosphotransferase that is found in the mitochondrial matrix. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.39

Clinical Summary— AK3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

45 VUS of 51 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.39LOEUF

pLI 0.000

Z-score 0.73

OE 0.74 (0.42–1.39)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.97Z-score

OE missense 1.50 (1.33–1.69)

185 obs / 123.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.74 (0.42–1.39)

0≤0.351.4

Missense OE?1.50 (1.33–1.69)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 7 / 9.4Missense obs/exp: 185 / 123.5Syn Z: -1.55

This gene — mechanism propensity

0.78top 25%

GOF

0.6345th %ile

LOF

0.2776th %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

51 submitted variants in ClinVar

ClinVar

Classification Summary

VUS45

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	45	45
Likely Benign	0	0
Benign	0	0
Total	45	45

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

View in ClinVar →

170 pathogenic / likely-pathogenic (of 189) ClinVar copy-number / structural variants overlap AK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →