Is PTEN p.Cys218Ter (c.654C>A) pathogenic?

PTEN p.Cys218Ter (c.654C>A) is classified Pathogenic in PTEN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-09-29). Absent from gnomAD v4.1; Associated with Cowden syndrome 1.

What condition is associated with PTEN p.Cys218Ter (c.654C>A)?

PTEN p.Cys218Ter (c.654C>A) is associated with Cowden syndrome 1, macrocephaly-autism syndrome, familial meningioma (ClinVar).

How common is PTEN p.Cys218Ter (c.654C>A) in the general population?

PTEN p.Cys218Ter (c.654C>A) is absent from gnomAD v4.1 (gnomAD).

PTEN p.Cys218Ter

c.654C>A · rs1554825165 · VCV631516

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cowden syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.7, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Cys218Ter
Coding: c.654C>A
MANE Select: NM_000314
dbSNP: rs1554825165
Type: single nucleotide variant
Location: chr10:87957872 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 218: 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: macrocephaly-autism syndrome familial meningioma glioma susceptibility 2 PTEN hamartoma tumor syndrome prostate cancer, hereditary

Similar variants

PTEN p.Cys218Phe Uncertain significance ★★ ⚠ same residue
PTEN p.Cys218Ser Uncertain significance ★★ ⚠ same residue
PTEN p.Cys218Tyr Uncertain significance ★★ ⚠ same residue
PTEN p.Cys218Arg 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-cys218ter (accessed [today's date]).

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