Is PTEN p.Ile28Ser (c.83T>G) pathogenic?

PTEN p.Ile28Ser (c.83T>G) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PTEN p.Ile28Ser (c.83T>G)?

PTEN p.Ile28Ser (c.83T>G) is associated with hereditary neoplastic syndrome, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Ile28Ser (c.83T>G) in the general population?

PTEN p.Ile28Ser (c.83T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTEN p.Ile28Ser (c.83T>G)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

PTEN p.Ile28Ser

c.83T>G · rs1355570425 · VCV1003503

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 8% in PTEN
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -15.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.21	acceptor loss, 10 bp away · masked 0 · deltas
Pangolin	Δ0.25	loss · gain 0.10 · agrees with SpliceAI · independent
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	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

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.Ile28Ser
Coding: c.83T>G
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

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

Also linked: PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Ile28Val Uncertain significance ★★ ⚠ same residue
PTEN p.Ile28Met Uncertain significance ★ ⚠ same residue
PTEN p.Ile28Thr 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-ile28ser (accessed [today's date]).

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