Is PTEN p.Pro354Arg (c.1061C>G) pathogenic?

PTEN p.Pro354Arg (c.1061C>G) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-12). AlphaMissense: likely benign (0.2094); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PTEN p.Pro354Arg (c.1061C>G)?

PTEN p.Pro354Arg (c.1061C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Pro354Arg (c.1061C>G) in the general population?

PTEN p.Pro354Arg (c.1061C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTEN p.Pro354Arg (c.1061C>G)?

AlphaMissense predicts likely benign (score 0.2094) — an in-silico prediction, not a clinical call.

PTEN p.Pro354Arg

c.1061C>G · rs375709098 · VCV1780374

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2094 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2094	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -7.11	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 6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.34	unconstrained · MANE · 43 bp · p 0.16 · regional, not allelic
Overall
CADD	24.5	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

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.Pro354Arg
Coding: c.1061C>G
MANE Select: NM_000314
dbSNP: rs375709098
Type: single nucleotide variant
Location: chr10:87965321 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 354: a UniProt-annotated variant site (in mcephas); the 'disordered' region

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

Similar variants

PTEN p.Pro354Leu Uncertain significance ★★★ ⚠ same residue
PTEN p.Pro354Gln Likely benign ★★★ same residue
PTEN p.Pro354= Conflicting classifications of pathogenicity ★ same residue
PTEN p.Pro354Ser Likely benign ★ 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-pro354arg (accessed [today's date]).

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