Is AKT2 p.Pro45Ala (c.133C>G) pathogenic?

AKT2 p.Pro45Ala (c.133C>G) is classified Uncertain significance in AKT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.0504); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with AKT2 p.Pro45Ala (c.133C>G)?

AKT2 p.Pro45Ala (c.133C>G) is associated with Inborn genetic diseases (ClinVar).

How common is AKT2 p.Pro45Ala (c.133C>G) in the general population?

AKT2 p.Pro45Ala (c.133C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AKT2 p.Pro45Ala (c.133C>G)?

AlphaMissense predicts likely benign (score 0.0504) — an in-silico prediction, not a clinical call.

AKT2 p.Pro45Ala

c.133C>G · VCV3850891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0504 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0504	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -5.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 27 kb · p 3.2e-08 · regional, not allelic
Overall
CADD	18.51	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AKT2
Protein: p.Pro45Ala
Coding: c.133C>G
MANE Select: NM_001626
Type: single nucleotide variant
Location: chr19:40256968 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 19 PDB
Residue 45: the ph domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AKT2 p.Gln429Arg Uncertain significance ★★ ⚠ same condition
AKT2 p.Ala445Val Uncertain significance ★ ⚠ same condition
AKT2 p.Arg170Trp Uncertain significance ★ ⚠ same condition
AKT2 p.Arg245Cys Uncertain significance ★ ⚠ same condition
AKT2 p.Arg392Trp Uncertain significance ★ ⚠ same condition
AKT2 p.Asp192Gly Uncertain significance ★ ⚠ same condition
AKT2 p.Asp284His Uncertain significance ★ ⚠ same condition
AKT2 p.Glu193Lys 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-pro45ala (accessed [today's date]).

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