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

The protein encoded by this gene is a member of the AKT, also called PKB, serine/threonine protein kinase family. AKT kinases are known to be regulators of cell signaling in response to insulin and growth factors. They are involved in a wide variety of biological processes including cell proliferation, differentiation, apoptosis, tumorigenesis, as well as glycogen synthesis and glucose uptake. This kinase has been shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). Alternatively splice transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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

18 unique Pathogenic / Likely Pathogenic· 102 VUS of 312 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 OE?0.04 (0.01–0.18)

0≤0.351.4

Missense OE?0.30 (0.25–0.36)

0≤0.61.4

Synonymous OE?0.98

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

This gene — mechanism propensity

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 · 72% of P/LP are missense

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.1

LOFHaploinsufficiency of AKT3 gene causing microcephaly and psychomotor delay in a patient with 1q43q44 microdeletion.2

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

References

ClinVar Variant Classifications

312 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic9

VUS102

Likely Benign128

Benign26

Conflicting12

Pathogenic

Likely Pathogenic

102

VUS

128

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	6	2	0	9
Likely Pathogenic	0	7	2	0	9
VUS	9	79	13	1	102
Likely Benign	2	2	69	55	128
Benign	1	0	22	3	26
Conflicting	—				12
Total	13	94	108	59	286

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

View in ClinVar →

97 pathogenic / likely-pathogenic (of 126) ClinVar copy-number / structural variants overlap AKT3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →