Is AKT2 p.Pro375= (c.1125C>T) pathogenic?

AKT2 p.Pro375= (c.1125C>T) is classified Likely benign in AKT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). Rare (popmax 0.107%, eas); Associated with type 2 diabetes mellitus.

What condition is associated with AKT2 p.Pro375= (c.1125C>T)?

AKT2 p.Pro375= (c.1125C>T) is associated with type 2 diabetes mellitus, hypoinsulinemic hypoglycemia and body hemihypertrophy (ClinVar).

How common is AKT2 p.Pro375= (c.1125C>T) in the general population?

AKT2 p.Pro375= (c.1125C>T) is rare (popmax 0.107%, eas) (gnomAD).

AKT2 p.Pro375=

c.1125C>T · rs145977456 · VCV2940916

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4.5
Overall
CADD	0.328	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.107% East Asian · 48/44,874 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.0108% 174/1,613,634 alleles · rare exomes 157/1,461,482 · genomes 17/152,152 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	935
Middle Eastern	0.033%	3,034
Remaining individualsnot grpmax-eligible	0.0256%	3,905
European (non-Finnish)	0.00864%	11,569
African / African-American	0.00534%	18,730
Admixed American	0.00167%	59,994
South Asian	0.0011%	91,090

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AKT2
Protein: p.Pro375=
Coding: c.1125C>T
MANE Select: NM_001626
dbSNP: rs145977456
Type: single nucleotide variant
Location: chr19:40235940 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 19 PDB
Residue 375: the protein kinase domain; an α-helix

Full AKT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoinsulinemic hypoglycemia and body hemihypertrophy

Similar variants

AKT2 c.709-3C>G Uncertain significance ★★ same condition
AKT2 c.960+3G>T Uncertain significance ★★ same condition
AKT2 p.Ala214Val Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg113Trp Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg15His Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg253Gln Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg347Cys Uncertain significance ★★ ⚠ same condition
AKT2 p.Asp399Asn Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/akt2-p-pro375 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown