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.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 1.39
Clinical SummaryAK3
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.39LOEUF
pLI 0.000
Z-score 0.73
OE 0.74 (0.421.39)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-1.97Z-score
OE missense 1.50 (1.331.69)
185 obs / 123.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.74 (0.421.39)
00.351.4
Missense OE1.50 (1.331.69)
00.61.4
Synonymous OE1.28
01.21.6
LoF obs/exp: 7 / 9.4Missense obs/exp: 185 / 123.5Syn Z: -1.55
DN
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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

AK3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
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