Is PTEN p.Ile280Val (c.838A>G) pathogenic?

PTEN p.Ile280Val (c.838A>G) is classified Uncertain significance in PTEN (ClinVar, Expert panel, 14 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.2652); Very rare (popmax 8.48e-05%, nfe); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Ile280Val (c.838A>G)?

PTEN p.Ile280Val (c.838A>G) is associated with PTEN hamartoma tumor syndrome, Cowden syndrome 1, glioma susceptibility 2 (ClinVar).

How common is PTEN p.Ile280Val (c.838A>G) in the general population?

PTEN p.Ile280Val (c.838A>G) is very rare (popmax 8.48e-05%, nfe) (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.Ile280Val (c.838A>G)?

AlphaMissense predicts likely benign (score 0.2652) — an in-silico prediction, not a clinical call.

PTEN p.Ile280Val

c.838A>G · rs1474354667 · VCV468719

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.2652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

Uncertain Significance for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):

PM2 PP2 BS3

Curation rationale (ClinGen, verbatim)

PTEN c.838A>G (p.Ile280Val) is currently classified as a variant of uncertain significance 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). PM2: present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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. BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 29706350, PMID 29785012)

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

Computational evidence

Protein change
AlphaMissense	0.2652	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -2.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 2.4, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,716 alleles

Overall 6.85e-05% 1/1,460,876 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.Ile280Val
Coding: c.838A>G
MANE Select: NM_000314
dbSNP: rs1474354667
Type: single nucleotide variant
Location: chr10:87960930 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 280: a β-strand; the c2 tensin-type domain; a UniProt-annotated variant site (in mcephas)

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

Also linked: Cowden syndrome 1 glioma susceptibility 2 hereditary neoplastic syndrome Cowden disease

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Ile280Leu Uncertain significance ★★ ⚠ same residue
PTEN p.Ile280Lys Uncertain significance ★ ⚠ same residue
PTEN p.Ile280fs Pathogenic ★ same residue
PTEN p.Ile280Met Uncertain significance ★ ⚠ 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-ile280val (accessed [today's date]).

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