AKT3

Chr 1

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

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.

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMegalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes · AD · ClinGen 2021
Strong · megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 · AD · Genomics England PanelApp
Strong · megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 · AD · G2P
Limited · microcephaly · AD · ClinGen 2021 — not for standalone diagnostic reporting

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P/LP submissions

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P/LP missense

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LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (2)

gnomad: Error: gnomAD API error: 400

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in AKT3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 290

289 rare PASS variants

Rare truncating (LoF)

1 in 1,000

46 rare PASS variants

Rare synonymous (reference)

1 in 250

222 rare PASS variants

Rare missense and truncating variants are carried at similar rates in AKT3; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 340	1 in 790
South Asian	~43k	1 in 760	1 in 4,600
Remaining (unassigned)	~30k	1 in 910	1 in 3,000
European (Finnish)	~27k	1 in 540	1 in 710
Admixed American	~22k	1 in 230	1 in 830
African / African American	~21k	1 in 320	1 in 670
East Asian	~20k	1 in 340	1 in 2,200
Ashkenazi Jewish	~13k	1 in 160	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 480	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 13 coding exons well covered in gnomAD exomes; exons 4, 6, 8, 13 marginal. Genomes: all 13.? see exons ↓