Is AKT3 p.Asp280= (c.840C>T) pathogenic?

AKT3 p.Asp280= (c.840C>T) is classified Likely benign in AKT3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0827%, mid); Associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2.

What condition is associated with AKT3 p.Asp280= (c.840C>T)?

AKT3 p.Asp280= (c.840C>T) is associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (ClinVar).

How common is AKT3 p.Asp280= (c.840C>T) in the general population?

AKT3 p.Asp280= (c.840C>T) is ultra-rare (popmax 0.0827%, mid) (gnomAD).

AKT3 p.Asp280=

c.840C>T · rs201347487 · VCV475214

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0827%, 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 2.7	GERP -0.82, phastCons 1
Overall
CADD	6.373	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0827% Middle Eastern · 5/6,048 alleles

Filtering AF 0.0326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.00788% 127/1,612,176 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0827%	1,210
Admixed American	0.0353%	2,834
Remaining individualsnot grpmax-eligible	0.0192%	5,202
European (non-Finnish)	0.00738%	13,555
African / African-American	0.00267%	37,474

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.Asp280=
Coding: c.840C>T
MANE Select: NM_005465
dbSNP: rs201347487
Type: single nucleotide variant
Location: chr1:243563828 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 82.42 · 2 PDB
Residue 280: the protein kinase domain

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.Asp280Tyr Uncertain significance ★ ⚠ same residue
AKT3 p.Asp280Gly Uncertain significance ★ ⚠ 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

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-asp280 (accessed [today's date]).

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