Is PTEN p.Glu353Lys (c.1057G>A) pathogenic?

PTEN p.Glu353Lys (c.1057G>A) is classified Uncertain significance in PTEN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-24). AlphaMissense: ambiguous (0.5082); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Glu353Lys (c.1057G>A)?

PTEN p.Glu353Lys (c.1057G>A) is associated with PTEN hamartoma tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Glu353Lys (c.1057G>A) in the general population?

PTEN p.Glu353Lys (c.1057G>A) is absent from gnomAD v4.1 (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

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

What do computational predictors say about PTEN p.Glu353Lys (c.1057G>A)?

AlphaMissense predicts ambiguous (score 0.5082) — an in-silico prediction, not a clinical call.

PTEN p.Glu353Lys

c.1057G>A · rs1554826035 · VCV2567264

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5082 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

PTEN hamartoma tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.5082	ambiguous
REVEL	0.433	indeterminate
SaProt	LLR -6.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.34	unconstrained · MANE · 43 bp · p 0.16 · regional, not allelic
Overall
CADD	25.1	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

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: PTEN
Protein: p.Glu353Lys
Coding: c.1057G>A
MANE Select: NM_000314
dbSNP: rs1554826035
Type: single nucleotide variant
Location: chr10:87965317 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 353: a UniProt-annotated variant site (in mcephas); the 'disordered' region

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

Disease context

PTEN hamartoma tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For PTEN hamartoma tumor syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

PTEN p.Glu353Gly Uncertain significance ★ ⚠ same residue
PTEN p.Glu353= Likely benign ★ same residue
PTEN p.Glu353del Uncertain significance ★★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition
PTEN c.1027-1852A>G Likely pathogenic ★★★ same condition
PTEN c.1027-1G>A Pathogenic ★★★ same condition
PTEN c.165-1G>A Likely pathogenic ★★★ same condition
PTEN c.165-1G>C Pathogenic ★★★ 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/pten-p-glu353lys (accessed [today's date]).

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