Is AKT2 p.Phe409= (c.1227C>T) pathogenic?

AKT2 p.Phe409= (c.1227C>T) is classified Likely benign in AKT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). Very rare (popmax 0.0022%, sas); Associated with type 2 diabetes mellitus.

What condition is associated with AKT2 p.Phe409= (c.1227C>T)?

AKT2 p.Phe409= (c.1227C>T) is associated with type 2 diabetes mellitus, hypoinsulinemic hypoglycemia and body hemihypertrophy (ClinVar).

How common is AKT2 p.Phe409= (c.1227C>T) in the general population?

AKT2 p.Phe409= (c.1227C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

AKT2 p.Phe409=

c.1227C>T · rs774681177 · VCV2126287

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

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 6.7	GERP 0.066, phastCons 1
Overall
CADD	13.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,074 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,614,056 alleles · very rare exomes 2/1,461,780 · genomes 0/152,276 · joint denominator

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.Phe409=
Coding: c.1227C>T
MANE Select: NM_001626
dbSNP: rs774681177
Type: single nucleotide variant
Location: chr19:40235299 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 19 PDB
Residue 409: 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-phe409 (accessed [today's date]).

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