AKT3

Chr 1AD

AKT serine/threonine kinase 3

Also known as: MPPH, MPPH2, PKB-GAMMA, PKBG, PRKBG, RAC-PK-gamma, RAC-gamma, STK-2

NCBI Gene: 10000 ENSG00000117020 UniProt: Q9Y243 OMIM: 611223

The protein is a serine/threonine kinase that regulates cell signaling in response to insulin and growth factors, controlling cell proliferation, differentiation, apoptosis, and glucose metabolism. Loss-of-function mutations cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.181 OMIM phenotype

VCEP Guidelines: Brain MalformationsReleased

View Specifications ClinGen Panel

Clinical Summary— AKT3

🧬

Gene-Disease Validity (ClinGen)

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

115 unique Pathogenic / Likely Pathogenic· 128 VUS of 437 total submissions

💊

Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — AKT3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.18LOEUF

pLI 1.000

Z-score 4.61

OE 0.04 (0.01–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.95Z-score

OE missense 0.30 (0.25–0.36)

76 obs / 252.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.04 (0.01–0.18)

0≤0.351.4

Missense OE0.30 (0.25–0.36)

0≤0.61.4

Synonymous OE0.98

0≤1.21.6

LoF obs/exp: 1 / 26.7Missense obs/exp: 76 / 252.4Syn Z: 0.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongAKT3-related hemimegalencephalyOTHERAD

0.3097th %ile

GOF

0.4579th %ile

LOF

0.72top 10%

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

LOFprediction above median · 1 literature citation · LOEUF 0.18

GOF1 literature citation

Literature Evidence

GOFWe found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G->A, creating p.E17K) that was not present in the patient's blood cells.PMID:22500628

LOFHaploinsufficiency of AKT3 gene causing microcephaly and psychomotor delay in a patient with 1q43q44 microdeletion.PMID:31929334

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.