PTEN p.Ala34Pro
c.100G>C · rs1589617199 · VCV822002
ClinGen expert panel — PTEN VCEP
Pathogenic for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):
PM2_P PS3 PS4_P PP2 PP3_P
Curation rationale (ClinGen, verbatim)
PTEN c.100G>C (p.Ala34Pro) meets criteria to be classified as 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 Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of-3.02. Post 2020- yeast experiments (PMID 32350270)doesn’t conflict with Mighell et al 2018) PM2_P: Absent in large sequenced populations PP3_P: REVEL score > 0.7 (score of this variant =0.962) PS4_P:Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor: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.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9995 | likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN |
|---|---|---|
| REVEL | 0.962 | strongly pathogenic-leaning |
| SaProt | LLR -12.52 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>T here scores Δ0.37 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.5, 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.Ala34Pro
- Coding
- c.100G>C
- MANE Select
- NM_000314
- dbSNP
- rs1589617199
- Type
- single nucleotide variant
- Location
- chr10:87894045 (GRCh38)
- Gene constraint
- LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 83.76 · 12 PDB
- Residue 34
- a β-strand; the phosphatase tensin-type domain; 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 1hereditary neoplastic syndrome
For PTEN hamartoma tumor syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- PTEN p.Ala34Val Uncertain significance ★★ ⚠ same residue
- PTEN p.Ala34= Conflicting classifications of pathogenicity ★ same residue
- PTEN p.Ala34Thr 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-ala34pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown