Is PTEN p.Tyr155Cys (c.464A>G) pathogenic?

PTEN p.Tyr155Cys (c.464A>G) is classified Pathogenic in PTEN (ClinVar, Expert panel, 26 submitters; last evaluated 2019-11-22). AlphaMissense: likely pathogenic (0.9967); Very rare (popmax 0.00133%, afr); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Tyr155Cys (c.464A>G)?

PTEN p.Tyr155Cys (c.464A>G) is associated with PTEN hamartoma tumor syndrome, gastric cancer, hereditary breast ovarian cancer syndrome (ClinVar).

How common is PTEN p.Tyr155Cys (c.464A>G) in the general population?

PTEN p.Tyr155Cys (c.464A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PTEN p.Tyr155Cys (c.464A>G)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

PTEN p.Tyr155Cys

c.464A>G · rs1060500126 · VCV404168

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 26 submitters

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

Pathogenic for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):

PM6_S PM2 PS3 PS4 PP2

Curation rationale (ClinGen, verbatim)

PTEN c.464A>G (p.Tyr155Cys) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 21828076, 10866302, 29706350) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 23399955, internal laboratory contributors SCV000579967.3, ClinVar Organization ID: 19864) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957) PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic ✓ concordant with ClinVar
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -12.07	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00133% African / African-American · 1/75,026 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,460,882 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,026
European (non-Finnish)	0.00017%	589,564

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.Tyr155Cys
Coding: c.464A>G
MANE Select: NM_000314
dbSNP: rs1060500126
Type: single nucleotide variant
Location: chr10:87933223 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 155: 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)p4)

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

Disease context

PTEN hamartoma tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer hereditary breast ovarian cancer syndrome Cowden syndrome 1 macrocephaly-autism syndrome glioma susceptibility 2 hereditary neoplastic syndrome Cowden disease papillary tumor of the pineal region

For PTEN hamartoma tumor syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

PTEN p.Tyr155Asn Likely pathogenic ★★ same residue
PTEN p.Tyr155His Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Tyr155Ser Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Tyr155Ter Pathogenic ★★ same residue
PTEN p.Tyr155Phe Uncertain significance ★ ⚠ same residue
PTEN p.Tyr155fs Pathogenic ★ same residue
PTEN p.Tyr155Asp Likely 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-tyr155cys (accessed [today's date]).

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