Is PTEN p.Asp22Tyr (c.64G>T) pathogenic?

PTEN p.Asp22Tyr (c.64G>T) is classified Likely pathogenic in PTEN (ClinVar, Expert panel, 3 submitters; last evaluated 2026-06-16). AlphaMissense: likely pathogenic (0.9937); Very rare (popmax 0.0011%, sas); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Asp22Tyr (c.64G>T)?

PTEN p.Asp22Tyr (c.64G>T) is associated with PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Asp22Tyr (c.64G>T) in the general population?

PTEN p.Asp22Tyr (c.64G>T) is very rare (popmax 0.0011%, sas) (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.Asp22Tyr (c.64G>T)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

PTEN p.Asp22Tyr

c.64G>T · rs876660420 · VCV468706

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

PM2_Supporting PS2 PP2 PP3 PM5

Curation rationale (ClinGen, verbatim)

PTEN c.64G>T (p.Asp22Tyr) meets criteria to be classified as Likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.2.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor SCV003923984.2). PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 233456, SCV004183305.1). 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. PP3: REVEL score > 0.7 (score of this variant = 0.957) PM2_supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).

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

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic ✓ concordant with ClinVar
REVEL	0.957	strongly pathogenic-leaning
SaProt	LLR -14.34	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 1.9, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-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

Grpmax group 0.0011% South Asian · 1/91,040 alleles

Overall 6.84e-05% 1/1,461,742 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.Asp22Tyr
Coding: c.64G>T
MANE Select: NM_000314
dbSNP: rs876660420
Type: single nucleotide variant
Location: chr10:87864533 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 22: a turn; the phosphatase tensin-type domain

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

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Asp22His Likely pathogenic ★★★ same residue
PTEN p.Asp22= Likely benign ★★ same residue
PTEN p.Asp22Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Asp22_Leu23insTer Pathogenic ★ same residue
PTEN p.Asp22Glu Uncertain significance ★★ ⚠ same residue
PTEN p.Asp22Val Likely pathogenic ★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition
PTEN c.1027-1852A>G 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-asp22tyr (accessed [today's date]).

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