Is PTEN p.Leu100Phe (c.298C>T) pathogenic?

PTEN p.Leu100Phe (c.298C>T) is classified Likely pathogenic in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-01). AlphaMissense: likely pathogenic (0.9398); Very rare (popmax 8.48e-05%, nfe); Associated with Triple-negative breast cancer.

What condition is associated with PTEN p.Leu100Phe (c.298C>T)?

PTEN p.Leu100Phe (c.298C>T) is associated with Triple-negative breast cancer (ClinVar).

How common is PTEN p.Leu100Phe (c.298C>T) in the general population?

PTEN p.Leu100Phe (c.298C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PTEN p.Leu100Phe (c.298C>T)?

AlphaMissense predicts likely pathogenic (score 0.9398) — an in-silico prediction, not a clinical call.

PTEN p.Leu100Phe

c.298C>T · rs1589646100 · VCV1207213

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Triple-negative breast cancer

Computational evidence

Protein change
AlphaMissense	0.9398	likely pathogenic ✓ concordant with ClinVar
REVEL	0.682	pathogenic-leaning
SaProt	LLR -10.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	32.0	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 8.48e-05% European (non-Finnish) · 1/1,179,422 alleles

Overall 6.84e-05% 1/1,461,250 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.Leu100Phe
Coding: c.298C>T
MANE Select: NM_000314
dbSNP: rs1589646100
Type: single nucleotide variant
Location: chr10:87933057 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 100: an α-helix; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas)

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

Disease context

Triple-negative breast cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PTEN p.Leu100Val Uncertain significance ★★ ⚠ same residue
PTEN p.Leu100Ile Uncertain significance ★ ⚠ same residue
PTEN p.Leu100Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Leu100= Likely benign ★ same residue
PTEN p.Asp92Asn Likely pathogenic ★★ same condition
PTEN p.Tyr155Asp Likely pathogenic ★★ same condition
PTEN p.Cys105Ser Likely pathogenic ★ same condition
PTEN p.Glu150Lys 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-leu100phe (accessed [today's date]).

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