Is AKT2 p.Arg371Cys (c.1111C>T) pathogenic?

AKT2 p.Arg371Cys (c.1111C>T) is classified Uncertain significance in AKT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). AlphaMissense: ambiguous (0.5238); Very rare (popmax 0.005%, amr); Associated with hypoinsulinemic hypoglycemia and body hemihypertrophy.

How common is AKT2 p.Arg371Cys (c.1111C>T) in the general population?

AKT2 p.Arg371Cys (c.1111C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about AKT2 p.Arg371Cys (c.1111C>T)?

AlphaMissense predicts ambiguous (score 0.5238) — an in-silico prediction, not a clinical call.

AKT2 p.Arg371Cys

Q: What condition is associated with AKT2 p.Arg371Cys (c.1111C>T)?

AKT2 p.Arg371Cys (c.1111C>T) is associated with hypoinsulinemic hypoglycemia and body hemihypertrophy, type 2 diabetes mellitus (ClinVar).

Q: How is Hypoinsulinemic hypoglycemia and body hemihypertrophy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1111C>T · VCV4790747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5238 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hypoinsulinemic hypoglycemia and body hemihypertrophy

Computational evidence

Protein change
AlphaMissense	0.5238	ambiguous
REVEL	0.146	moderately benign-leaning
SaProt	LLR -15.15	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.039, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,176 bp · p 0.00027 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000991% 16/1,613,846 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00102%	98,337

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.Arg371Cys
Coding: c.1111C>T
MANE Select: NM_001626
Type: single nucleotide variant
Location: chr19:40235954 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 19 PDB
Residue 371: the protein kinase domain; a β-strand

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

Disease context

hypoinsulinemic hypoglycemia and body hemihypertrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus

For Hypoinsulinemic hypoglycemia and body hemihypertrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

AKT2 p.Arg371His Uncertain significance ★ ⚠ same residue
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

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-arg371cys (accessed [today's date]).

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