Is PTEN p.Ile67Met (c.201A>G) pathogenic?

PTEN p.Ile67Met (c.201A>G) is classified Uncertain significance in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-08). AlphaMissense: likely pathogenic (0.9692); Absent from gnomAD v4.1; Associated with Cowden syndrome 1.

What condition is associated with PTEN p.Ile67Met (c.201A>G)?

PTEN p.Ile67Met (c.201A>G) is associated with Cowden syndrome 1, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Ile67Met (c.201A>G) in the general population?

PTEN p.Ile67Met (c.201A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTEN p.Ile67Met (c.201A>G)?

AlphaMissense predicts likely pathogenic (score 0.9692) — an in-silico prediction, not a clinical call.

PTEN p.Ile67Met

c.201A>G · rs2132232357 · VCV2754588

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9692 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cowden syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9692	likely pathogenic
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -11.27	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 9.3	GERP 2.8, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ile67Met
Coding: c.201A>G
MANE Select: NM_000314
dbSNP: rs2132232357
Type: single nucleotide variant
Location: chr10:87925549 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 67: a β-strand; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1)

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

Disease context

Cowden syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Ile67= Likely benign ★★ same residue
PTEN p.Ile67Arg Likely pathogenic ★ same residue
PTEN p.Ile67Leu Uncertain significance ★ ⚠ same residue
PTEN p.Ile67Lys Uncertain significance ★ ⚠ same residue
PTEN p.Ile67Thr Uncertain significance ★ ⚠ same residue
PTEN p.Ile67Val Uncertain significance ★ ⚠ same residue
PTEN p.Ile67fs Pathogenic ★ same residue
PTEN c.1026+1G>A 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-ile67met (accessed [today's date]).

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