Is PTEN p.Ser361Arg (c.1081A>C) pathogenic?

PTEN p.Ser361Arg (c.1081A>C) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.7934); Very rare (popmax 0.00223%, eas); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Ser361Arg (c.1081A>C)?

PTEN p.Ser361Arg (c.1081A>C) is associated with PTEN hamartoma tumor syndrome, glioma susceptibility 2, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Ser361Arg (c.1081A>C) in the general population?

PTEN p.Ser361Arg (c.1081A>C) is very rare (popmax 0.00223%, eas) (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.Ser361Arg (c.1081A>C)?

AlphaMissense predicts likely pathogenic (score 0.7934) — an in-silico prediction, not a clinical call.

PTEN p.Ser361Arg

c.1081A>C · rs1472028496 · VCV492314

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PTEN hamartoma tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.7934	likely pathogenic
REVEL	0.437	indeterminate
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 1.34	unconstrained · MANE · 43 bp · p 0.16 · regional, not allelic
Overall
CADD	23.4	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 0.00223% East Asian · 1/44,780 alleles

Overall 0.000186% 3/1,609,758 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,131
East Asiangrpmax	0.00223%	44,780

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser361Arg
Coding: c.1081A>C
MANE Select: NM_000314
dbSNP: rs1472028496
Type: single nucleotide variant
Location: chr10:87965341 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 361: 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

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.Ser361Gly Uncertain significance ★ ⚠ same residue
PTEN p.Ser361Ile Uncertain significance ★ ⚠ same residue
PTEN p.Ser361Thr Uncertain significance ★ ⚠ same residue
PTEN p.Ser361= 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-ser361arg (accessed [today's date]).

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