Is PTEN p.Leu345Val (c.1033C>G) pathogenic?

PTEN p.Leu345Val (c.1033C>G) is classified Uncertain significance in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.372); Very rare (popmax 0.000255%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PTEN p.Leu345Val (c.1033C>G)?

PTEN p.Leu345Val (c.1033C>G) is associated with hereditary neoplastic syndrome, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Leu345Val (c.1033C>G) in the general population?

PTEN p.Leu345Val (c.1033C>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about PTEN p.Leu345Val (c.1033C>G)?

AlphaMissense predicts ambiguous (score 0.372) — an in-silico prediction, not a clinical call.

PTEN p.Leu345Val

c.1033C>G · rs1114167639 · VCV428214

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.372 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.372	ambiguous
REVEL	0.625	indeterminate
SaProt	LLR -10.84	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.47, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	21.6	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 0.000255% European (non-Finnish) · 3/1,176,972 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,456,894 alleles · very rare

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: PTEN
Protein: p.Leu345Val
Coding: c.1033C>G
MANE Select: NM_000314
dbSNP: rs1114167639
Type: single nucleotide variant
Location: chr10:87965293 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 345: a UniProt-annotated variant site (in glioblastoma; reduced tumor suppressor activity; loss of interaction with nop53; decreased phosphorylation at s-380; decreased stability; loss of phosphatase activity towards ins(1,3,4,5)p4; reduced ability to inactivate akt/pkb; retains ability to bind phospholipid membranes); a β-strand; the c2 tensin-type domain; the 'required for interaction with nop53' region; a UniProt-annotated variant site (in mcephas)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Leu345Pro Pathogenic ★★★ same residue
PTEN p.Leu345Arg Uncertain significance ★★★ ⚠ same residue
PTEN p.Leu345= Benign/Likely benign ★★ same residue
PTEN p.Leu345Gln 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

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-leu345val (accessed [today's date]).

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