PTEN p.Leu70Pro
c.209T>C · rs121909226 · VCV7826
ClinGen expert panel — PTEN VCEP
Likely Pathogenic for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Supporting PS3_Moderate PP2 PP3
Curation rationale (ClinGen, verbatim)
PTEN c.209T>C (p.Leu70Pro) 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 3.1.0). 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 29706350) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor(s) ClinVar Organization ID: 26957)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 1 | likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN |
|---|---|---|
| REVEL | 0.988 | strongly pathogenic-leaning |
| SaProt | LLR -14.99 | 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 7.9 | GERP 2.8, 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
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.Leu70Pro
- Coding
- c.209T>C
- MANE Select
- NM_000314
- dbSNP
- rs121909226
- Type
- single nucleotide variant
- Location
- chr10:87925557 (GRCh38)
- Gene constraint
- LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 83.76 · 12 PDB
- Residue 70
- a β-strand; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1)
Disease context
PTEN hamartoma tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: Cowden syndrome 1prostate cancermacrocephaly-autism syndromefamilial meningiomaglioma susceptibility 2hereditary neoplastic syndrome
For PTEN hamartoma tumor syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- PTEN p.Leu70Phe Uncertain significance ★★ ⚠ same residue
- PTEN p.Leu70Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
- PTEN p.Leu70Ile Uncertain significance ★ ⚠ same residue
- PTEN p.Leu70fs 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
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-leu70pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown