PTEN p.Arg378fs
c.1133_1136del · rs1064794878 · VCV421055
ClinGen expert panel — PTEN VCEP
Uncertain Significance for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting PM4
Curation rationale (ClinGen, verbatim)
NM_000314.8(PTEN):c.1133_1136del (p.Arg378IlefsTer37) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2_P: Absent in large sequenced populations (PMID 27535533). PM4: Variant causes protein extension (NM_000314.4)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | escapes | premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 1.6, phastCons 1 |
| Region caveats | ||
| Repeat context | seg dup | · reads may not map uniquely · confidence, not pathogenicity |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
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.Arg378fs
- Coding
- c.1133_1136del
- MANE Select
- NM_000314
- dbSNP
- rs1064794878
- Type
- Deletion
- Location
- chr10:87965390 (GRCh38)
- Gene constraint
- LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 83.76 · 12 PDB
- Residue 378
- a UniProt-annotated variant site (in mcephas); the 'disordered' region
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.Arg378_Tyr379insTer Likely pathogenic ★ same residue
- PTEN p.Arg378= Likely benign ★★ same residue
- PTEN p.Arg378Gly Uncertain significance ★ ⚠ same residue
- PTEN c.209+4_209+7del Pathogenic ★★★ same condition
- PTEN c.210-2_211del Pathogenic ★★★ same condition
- PTEN c.801+1del Pathogenic ★★★ same condition
- PTEN c.802-2del Pathogenic ★★★ same condition
- PTEN p.Asn329fs 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-arg378fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown