Is PTEN p.Cys136Phe (c.407G>T) pathogenic?

PTEN p.Cys136Phe (c.407G>T) is classified Pathogenic/Likely pathogenic in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-18). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with Cowden syndrome 1.

What condition is associated with PTEN p.Cys136Phe (c.407G>T)?

PTEN p.Cys136Phe (c.407G>T) is associated with Cowden syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Cys136Phe (c.407G>T) in the general population?

PTEN p.Cys136Phe (c.407G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTEN p.Cys136Phe (c.407G>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

PTEN p.Cys136Phe

c.407G>T · rs786204859 · VCV1737618

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9996 · 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	0.9996	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -16.09	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	34.0	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

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.Cys136Phe
Coding: c.407G>T
MANE Select: NM_000314
dbSNP: rs786204859
Type: single nucleotide variant
Location: chr10:87933166 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 136: an α-helix; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1; loss of phosphatase activity towards ins(1,3,4,5)p3)

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: hereditary neoplastic syndrome

Similar variants

PTEN p.Cys136Trp Pathogenic ★★★ same residue
PTEN p.Cys136Tyr Pathogenic ★★★ same residue
PTEN p.Cys136Arg Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Cys136= Benign/Likely benign ★★ same residue
PTEN p.Cys136Gly 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

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-cys136phe (accessed [today's date]).

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