Is AKT2 p.Phe219= (c.657C>T) pathogenic?

AKT2 p.Phe219= (c.657C>T) is classified Likely benign in AKT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-31). Ultra-rare (popmax 0.0165%, mid).

How common is AKT2 p.Phe219= (c.657C>T) in the general population?

AKT2 p.Phe219= (c.657C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

AKT2 p.Phe219=

c.657C>T · rs371334732 · VCV730785

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 7.3	GERP 2.2, phastCons 1
Overall
CADD	15.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00109% 16/1,461,572 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)	0.00102%	98,326

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.Phe219=
Coding: c.657C>T
MANE Select: NM_001626
dbSNP: rs371334732
Type: single nucleotide variant
Location: chr19:40238956 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 19 PDB
Residue 219: the protein kinase domain; a β-strand

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

Similar variants

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

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-phe219 (accessed [today's date]).

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