Is PTEN p.Val275Ile (c.823G>A) pathogenic?

PTEN p.Val275Ile (c.823G>A) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.1311); Very rare (popmax 0.00139%, afr); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Val275Ile (c.823G>A)?

PTEN p.Val275Ile (c.823G>A) is associated with PTEN hamartoma tumor syndrome, glioma susceptibility 2, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Val275Ile (c.823G>A) in the general population?

PTEN p.Val275Ile (c.823G>A) is very rare (popmax 0.00139%, afr) (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.Val275Ile (c.823G>A)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

PTEN p.Val275Ile

c.823G>A · rs1410198544 · VCV627703

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00139%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PTEN hamartoma tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -5.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	23.5	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 0.00139% African / African-American · 1/72,184 alleles

Overall 0.000685% 1/146,060 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.Val275Ile
Coding: c.823G>A
MANE Select: NM_000314
dbSNP: rs1410198544
Type: single nucleotide variant
Location: chr10:87960915 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 275: 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: glioma susceptibility 2 hereditary neoplastic syndrome

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Val275_Asn276insTer Pathogenic ★ same residue
PTEN p.Val275fs Pathogenic ★ same residue
PTEN p.Val275= Conflicting classifications of pathogenicity ★ same residue
PTEN p.Val275Ala 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-val275ile (accessed [today's date]).

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