Is PTEN p.Phe258= (c.774C>T) pathogenic?

PTEN p.Phe258= (c.774C>T) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-13). Very rare (popmax 0.000763%, nfe); Associated with Cowden syndrome 1.

What condition is associated with PTEN p.Phe258= (c.774C>T)?

PTEN p.Phe258= (c.774C>T) is associated with Cowden syndrome 1, hereditary neoplastic syndrome, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Phe258= (c.774C>T) in the general population?

PTEN p.Phe258= (c.774C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

PTEN p.Phe258=

c.774C>T · rs1554825246 · VCV536572

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

Cowden syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Overall
CADD	13.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,974 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,810 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.Phe258=
Coding: c.774C>T
MANE Select: NM_000314
dbSNP: rs1554825246
Type: single nucleotide variant
Location: chr10:87957992 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 258: a β-strand; the c2 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

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

Also linked: hereditary neoplastic syndrome PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Phe258fs Pathogenic ★ 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
PTEN c.209+4A>G Pathogenic ★★★ same condition
PTEN c.209+5G>C 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-phe258 (accessed [today's date]).

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