# NM_005465.7(AKT3):c.6C>T (p.Ser2=)

https://sugi.bio/variant/akt3-p-ser2

## Summary

**AKT3 p.Ser2= (c.6C>T)** is classified **Likely benign** in AKT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-09-28). Very rare (popmax 0.00223%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs1057523451 · 1 submitter · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the AKT3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AKT3](https://sugi.bio/atlas/gene/AKT3/) |
| Protein change (HGVS p.) | p.Ser2= |
| Coding change (HGVS c.) | c.6C>T |
| MANE Select transcript | [NM_005465](https://www.ncbi.nlm.nih.gov/nuccore/NM_005465) |
| dbSNP | [rs1057523451](https://www.ncbi.nlm.nih.gov/snp/rs1057523451/) |
| Variant type | single nucleotide variant |
| Location | chr1:243843165-243843165 (GRCh38) |
| ClinVar | [VCV389504](https://www.ncbi.nlm.nih.gov/clinvar/variation/389504/) |

**All HGVS expressions:** `LRG_1396:g.12915C>T`, `LRG_1396t1:c.6C>T`, `NC_000001.10:g.244006467G>A`, `NC_000001.11:g.243843165G>A`, `NG_029764.2:g.12915C>T`, `NM_001206729.2:c.6C>T`, `NM_001370074.1:c.6C>T`, `NM_005465.7:c.6C>T`, `NM_181690.2:c.6C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.603, GERP 1.19, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.61**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.20 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000124% · FAF99 9e-05% · 1/44,858 in the highest group · 8/1,613,396 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,858 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,458 |
| African / African-American | 0.00134% | 74,876 |
| European (non-Finnish) | 0.000424% | 235,949 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AKT3** population constraint: LOEUF 0.482, pLI 0.99015, missense-Z 4.235; ClinGen dosage — haploinsufficiency 1, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes** — Definitive (AD)
- **microcephaly** — Limited (AD)

## Protein context {#protein}

Residue **2** lies in a modified residue (n-acetylserine).

AlphaFold model confidence (whole protein): pLDDT 82.42, 52% of residues very-high.

**2 experimental structure(s)** (PDB): [2X18](https://www.rcsb.org/structure/2X18), [8ZXW](https://www.rcsb.org/structure/8ZXW).

## What this gene does {#gene-function}

*Describes the biological roles of AKT3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AKT3's established molecular role includes protein serine/threonine kinase activity. In Reactome, AKT3 is annotated in disease pathway(s) including **Constitutive Signaling by AKT1 E17K in Cancer**, **SARS-CoV-2 targets host intracellular signalling and regulatory pathways**.

**Disease mechanism (Reactome):** AKT3 loss or alteration is curated in [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400), [SARS-CoV-2 targets host intracellular signalling and regulatory pathways](https://reactome.org/content/detail/R-HSA-9755779).

### Pathways affected {#pathways}

AKT3 participates in **29 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | other |
| ⚕ [SARS-CoV-2 targets host intracellular signalling and regulatory pathways](https://reactome.org/content/detail/R-HSA-9755779) | other |
| [Inhibition of TSC complex formation by AKT (PKB)](https://reactome.org/content/detail/R-HSA-165181) | curated |
| [MTOR signalling](https://reactome.org/content/detail/R-HSA-165159) | curated |
| [AKT phosphorylates targets in the cytosol](https://reactome.org/content/detail/R-HSA-198323) | other |
| [AKT phosphorylates targets in the nucleus](https://reactome.org/content/detail/R-HSA-198693) | other |
| [AKT-mediated inactivation of FOXO1A](https://reactome.org/content/detail/R-HSA-211163) | other |
| [Activation of BAD and translocation to mitochondria ](https://reactome.org/content/detail/R-HSA-111447) | other |
| [CD28 dependent PI3K/Akt signaling](https://reactome.org/content/detail/R-HSA-389357) | other |
| [Co-inhibition by CTLA4](https://reactome.org/content/detail/R-HSA-389513) | other |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | other |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | other |
| [Downregulation of ERBB2:ERBB3 signaling](https://reactome.org/content/detail/R-HSA-1358803) | other |
| [Estrogen-dependent nuclear events downstream of ESR-membrane signaling](https://reactome.org/content/detail/R-HSA-9634638) | other |
| [FLT3 Signaling](https://reactome.org/content/detail/R-HSA-9607240) | other |
| [G beta:gamma signalling through PI3Kgamma](https://reactome.org/content/detail/R-HSA-392451) | other |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | other |
| [Negative regulation of the PI3K/AKT network](https://reactome.org/content/detail/R-HSA-199418) | other |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | other |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | other |
| [RUNX2 regulates genes involved in cell migration](https://reactome.org/content/detail/R-HSA-8941332) | other |
| [Regulation of PTEN stability and activity](https://reactome.org/content/detail/R-HSA-8948751) | other |
| [Regulation of TP53 Activity through Acetylation](https://reactome.org/content/detail/R-HSA-6804758) | other |
| [Regulation of TP53 Activity through Association with Co-factors](https://reactome.org/content/detail/R-HSA-6804759) | other |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | other |
| [Regulation of localization of FOXO transcription factors](https://reactome.org/content/detail/R-HSA-9614399) | other |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | other |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | other |
| [VEGFR2 mediated vascular permeability](https://reactome.org/content/detail/R-HSA-5218920) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine kinase activity, ATP binding.

**Biological process:** positive regulation of endothelial cell proliferation, signal transduction, regulation of mitochondrion organization, positive regulation of blood vessel endothelial cell migration, positive regulation of cell migration involved in sprouting angiogenesis, positive regulation of vascular endothelial cell proliferation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2016-09-28.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-09-28 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AKT3 variant pages (same residue, condition, or type): [AKT3 p.Glu17Lys](/variant/akt3-p-glu17lys), [AKT3 p.Glu361Gly](/variant/akt3-p-glu361gly), [AKT3 p.Lys168=](/variant/akt3-p-lys168), [AKT3 p.Arg465Trp](/variant/akt3-p-arg465trp), [AKT3 p.Asn229Ile](/variant/akt3-p-asn229ile), [AKT3 p.Asp322Asn](/variant/akt3-p-asp322asn), [AKT3 p.Ile128Met](/variant/akt3-p-ile128met), [AKT3 p.Pro424Leu](/variant/akt3-p-pro424leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 389504). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*