PTEN p.Pro95Leu
c.284C>T · rs786204856 · VCV189403
ClinGen expert panel — PTEN VCEP
Pathogenic for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):
PM6 PM2 PS4_Supporting PS3 PP2
Curation rationale (ClinGen, verbatim)
PTEN c.284C>T (p.Pro95Leu) 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, PMID 29706350) PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957) 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 ClinVar Organization ID 26957)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9984 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.929 | moderately pathogenic-leaning |
| SaProt | LLR -16.60 | 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 7.7 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 0.27 | constrained · MANE · 69 kb · p 6.5e-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
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.Pro95Leu
- Coding
- c.284C>T
- MANE Select
- NM_000314
- dbSNP
- rs786204856
- Type
- single nucleotide variant
- Location
- chr10:87933043 (GRCh38)
- Gene constraint
- LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 83.76 · 12 PDB
- Residue 95
- an α-helix; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas)
Disease context
PTEN hamartoma tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hereditary neoplastic syndrome
For PTEN hamartoma tumor syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- PTEN p.Pro95Thr Uncertain significance ★★★ ⚠ same residue
- PTEN p.Pro95Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
- PTEN p.Pro95Gln Uncertain significance ★ ⚠ same residue
- PTEN p.Pro95Ser 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
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-pro95leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown