Is PTEN p.Ser59Ter (c.176C>G) pathogenic?

PTEN p.Ser59Ter (c.176C>G) is classified Pathogenic in PTEN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-04). Absent from gnomAD v4.1; Associated with PTEN-related disorder.

What condition is associated with PTEN p.Ser59Ter (c.176C>G)?

PTEN p.Ser59Ter (c.176C>G) is associated with PTEN-related disorder, Cowden syndrome 1, macrocephaly-autism syndrome (ClinVar).

How common is PTEN p.Ser59Ter (c.176C>G) in the general population?

PTEN p.Ser59Ter (c.176C>G) is absent from gnomAD v4.1 (gnomAD).

PTEN p.Ser59Ter

c.176C>G · rs1060500116 · VCV404151

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

PTEN-related disorder

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 3 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Overall
CADD	40.0	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.Ser59Ter
Coding: c.176C>G
MANE Select: NM_000314
dbSNP: rs1060500116
Type: single nucleotide variant
Location: chr10:87925524 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 59: an α-helix; the phosphatase tensin-type domain

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

Disease context

PTEN-related disorder

Also linked: Cowden syndrome 1 macrocephaly-autism syndrome familial meningioma glioma susceptibility 2 hereditary neoplastic syndrome PTEN hamartoma tumor syndrome prostate cancer, hereditary

Similar variants

PTEN p.Ser59= Benign/Likely benign ★★ same residue
PTEN p.Ser59Leu Uncertain significance ★ ⚠ same residue
PTEN p.Ser59Pro Conflicting classifications of pathogenicity ★ ⚠ 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

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-ser59ter (accessed [today's date]).

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