# NM_001626.6(AKT2):c.1110G>T (p.Pro370=)

https://sugi.bio/variant/akt2-p-pro370

## Summary

**AKT2 p.Pro370= (c.1110G>T)** is classified **Benign/Likely benign** in AKT2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-19). Rare (popmax 0.254%, nfe); Associated with hypoinsulinemic hypoglycemia and body hemihypertrophy.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs41309435 · 5 submitters · 2 linked conditions · rare (popmax 0.254%, nfe)

## For patients & families {#patients}

This is a change in the AKT2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to hypoinsulinemic hypoglycemia and body hemihypertrophy.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | AKT2 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Hypoinsulinemic hypoglycemia and body hemihypertrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hemihypertrophy — Obligate (100%)
- Gynecomastia — Very frequent (99-80%)
- Hypoglycemic coma — Very frequent (99-80%)
- Large for gestational age — Very frequent (99-80%)
- Truncal obesity — Very frequent (99-80%)
- Nonketotic hypoglycemia — Very frequent (99-80%)
- Hypoketotic hypoglycemia — Very frequent (99-80%)
- Neonatal hypoglycemia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017352/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AKT2](https://sugi.bio/atlas/gene/AKT2/) |
| Protein change (HGVS p.) | p.Pro370= |
| Coding change (HGVS c.) | c.1110G>T |
| MANE Select transcript | [NM_001626](https://www.ncbi.nlm.nih.gov/nuccore/NM_001626) |
| dbSNP | [rs41309435](https://www.ncbi.nlm.nih.gov/snp/rs41309435/) |
| Variant type | single nucleotide variant |
| Location | chr19:40235955-40235955 (GRCh38) |
| ClinVar | [VCV466265](https://www.ncbi.nlm.nih.gov/clinvar/variation/466265/) |

**All HGVS expressions:** `LRG_1391:g.54404G>T`, `LRG_1391t1:c.1110G>T`, `NC_000019.10:g.40235955C>A`, `NC_000019.9:g.40741862C>A`, `NG_012038.2:g.54404G>T`, `NM_001243027.3:c.924G>T`, `NM_001243028.3:c.924G>T`, `NM_001330511.1:c.981G>T`, `NM_001626.6:c.1110G>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 -20, GERP -4.46 — fast-evolving / accelerated position
- CADD: **PHRED 0.477**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.254%** (nfe) · FAF95 0.246% · FAF99 0.243% · 2,993/1,180,014 in the highest group · 4,577/1,613,886 alleles overall — rare (popmax 0.254%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 2.16% | 46 |
| European (non-Finnish) (grpmax) | 0.254% | 394 |
| Remaining individuals (not grpmax-eligible) | 0.208% | 481 |
| Admixed American | 0.0683% | 1,464 |
| African / African-American | 0.0427% | 2,344 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0135% | 7,401 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**AKT2** population constraint: LOEUF 0.398, pLI 0.99996, missense-Z 3.4263; ClinGen dosage — haploinsufficiency 0, 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):

- **AKT2-related familial partial lipodystrophy** — Limited (AD)
- **hypoinsulinemic hypoglycemia and body hemihypertrophy** — Definitive (AD)

## Protein context {#protein}

Residue **370** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 82.79, 51% of residues very-high.

**19 experimental structure(s)** (PDB): [1GZK](https://www.rcsb.org/structure/1GZK), [1GZN](https://www.rcsb.org/structure/1GZN), [1GZO](https://www.rcsb.org/structure/1GZO), [1MRV](https://www.rcsb.org/structure/1MRV), [1MRY](https://www.rcsb.org/structure/1MRY), [1O6K](https://www.rcsb.org/structure/1O6K).

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

*Describes the biological roles of AKT2 (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:** AKT2's established molecular role includes protein serine/threonine kinase activity. p.Pro370= falls in the protein kinase domain. In Reactome, AKT2 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):** AKT2 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}

AKT2 participates in **33 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 |
| [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 AKT2](https://reactome.org/content/detail/R-HSA-165158) | 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 |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | 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 |
| [Inhibition of TSC complex formation by AKT (PKB)](https://reactome.org/content/detail/R-HSA-165181) | 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 |
| [PDE3B signalling](https://reactome.org/content/detail/R-HSA-165160) | 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 MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | 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 |
| [Translocation of SLC2A4 (GLUT4) to the plasma membrane](https://reactome.org/content/detail/R-HSA-1445148) | 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, molecular function activator activity.

**Biological process:** insulin receptor signaling pathway, negative regulation of long-chain fatty acid import across plasma membrane, positive regulation of glucose metabolic process, positive regulation of cell migration, positive regulation of fatty acid beta-oxidation, cellular response to insulin stimulus.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-01 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-07 |

## Associated conditions {#conditions}

[hypoinsulinemic hypoglycemia and body hemihypertrophy](https://sugi.bio/atlas/disease/hypoinsulinemic-hypoglycemia-and-body-hemihypertrophy/), [type 2 diabetes mellitus](https://sugi.bio/atlas/disease/type-2-diabetes-mellitus/).

**Reported phenotype names (ClinVar):** Hypoinsulinemic hypoglycemia and body hemihypertrophy, Type 2 diabetes mellitus, not provided, none provided, Hypoinsulinemic hypoglycemia and hemihypertrophy, Type II diabetes mellitus.

## Similar variants {#similar}

Related AKT2 variant pages (same residue, condition, or type): [AKT2 c.709-3C>G](/variant/akt2-c-709-minus-3c-g), [AKT2 c.960+3G>T](/variant/akt2-c-960-plus-3g-t), [AKT2 p.Ala214Val](/variant/akt2-p-ala214val), [AKT2 p.Arg113Trp](/variant/akt2-p-arg113trp), [AKT2 p.Arg15His](/variant/akt2-p-arg15his), [AKT2 p.Arg253Gln](/variant/akt2-p-arg253gln), [AKT2 p.Arg347Cys](/variant/akt2-p-arg347cys), [AKT2 p.Asp399Asn](/variant/akt2-p-asp399asn).

### 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 466265). 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.*