Is PTEN p.Ile28Thr (c.83T>C) pathogenic?

PTEN p.Ile28Thr (c.83T>C) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-17). AlphaMissense: likely pathogenic (0.9989); Very rare (popmax 6.86e-05%); Associated with Cowden syndrome 1.

What condition is associated with PTEN p.Ile28Thr (c.83T>C)?

PTEN p.Ile28Thr (c.83T>C) is associated with Cowden syndrome 1, macrocephaly-autism syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Ile28Thr (c.83T>C) in the general population?

PTEN p.Ile28Thr (c.83T>C) is very rare (popmax 6.86e-05%) (gnomAD).

What do computational predictors say about PTEN p.Ile28Thr (c.83T>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

PTEN p.Ile28Thr

c.83T>C · rs1355570425 · VCV1192170

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.86e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cowden syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic
REVEL	0.986	strongly pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.86e-05%

Overall 6.86e-05% 1/1,457,484 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.Ile28Thr
Coding: c.83T>C
MANE Select: NM_000314
dbSNP: rs1355570425
Type: single nucleotide variant
Location: chr10:87894028 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 28: a β-strand; the phosphatase tensin-type domain

Full PTEN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cowden syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: macrocephaly-autism syndrome hereditary neoplastic syndrome PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Ile28Val Uncertain significance ★★ ⚠ same residue
PTEN p.Ile28Met Uncertain significance ★ ⚠ same residue
PTEN p.Ile28Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Ile28fs 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-ile28thr (accessed [today's date]).

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