Is AKT3 p.Pro466= (c.1398G>A) pathogenic?

AKT3 p.Pro466= (c.1398G>A) is classified Benign in AKT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). Ultra-rare (popmax 0.0164%, mid); Associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2.

What condition is associated with AKT3 p.Pro466= (c.1398G>A)?

AKT3 p.Pro466= (c.1398G>A) is associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (ClinVar).

How common is AKT3 p.Pro466= (c.1398G>A) in the general population?

AKT3 p.Pro466= (c.1398G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

AKT3 p.Pro466=

c.1398G>A · rs150573714 · VCV1167219

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

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 -10	GERP -3.5
Overall
CADD	4.375	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00682% 110/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.1%	1,000
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0112%	8,926
African / African-American	0.00667%	14,982
European (non-Finnish)	0.00263%	38,064
East Asian	0.00223%	44,898
South Asian	0.0011%	91,066

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AKT3
Protein: p.Pro466=
Coding: c.1398G>A
MANE Select: NM_005465
dbSNP: rs150573714
Type: single nucleotide variant
Location: chr1:243505291 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 82.42 · 2 PDB
Residue 466: the agc-kinase c-terminal domain; the 'disordered' region

Full AKT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AKT3 p.Pro466Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
AKT3 p.Glu17Lys Pathogenic ★★★ same condition
AKT3 p.Glu361Gly Likely benign ★★★ ⚠ same condition
AKT3 p.Lys168= Likely benign ★★★ same condition
AKT3 p.Arg465Trp Pathogenic/Likely pathogenic ★★ same condition
AKT3 p.Asp322Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
AKT3 p.Pro424Leu Uncertain significance ★★ ⚠ same condition
AKT3 p.Tyr251Cys 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/akt3-p-pro466 (accessed [today's date]).

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