Is PTEN p.Ser305Arg (c.915T>G) pathogenic?

PTEN p.Ser305Arg (c.915T>G) is classified Uncertain significance in PTEN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-23). AlphaMissense: ambiguous (0.3859); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PTEN p.Ser305Arg (c.915T>G)?

PTEN p.Ser305Arg (c.915T>G) is associated with hereditary neoplastic syndrome, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Ser305Arg (c.915T>G) in the general population?

PTEN p.Ser305Arg (c.915T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PTEN p.Ser305Arg (c.915T>G)?

AlphaMissense predicts ambiguous (score 0.3859) — an in-silico prediction, not a clinical call.

PTEN p.Ser305Arg

c.915T>G · rs876658345 · VCV230040

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3859 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3859	ambiguous
REVEL	0.487	indeterminate
SaProt	LLR -7.67	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.21, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	21.5	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 8.48e-05% European (non-Finnish) · 1/1,179,864 alleles

Overall 6.84e-05% 1/1,461,626 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.Ser305Arg
Coding: c.915T>G
MANE Select: NM_000314
dbSNP: rs876658345
Type: single nucleotide variant
Location: chr10:87961007 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 305: 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

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

Also linked: PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Ser305Asn Uncertain significance ★★★ ⚠ same residue
PTEN p.Ser305Ile Uncertain significance ★★ ⚠ same residue
PTEN p.Ser305Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Ser305Thr Uncertain significance ★ ⚠ same residue
PTEN p.Ser305fs Pathogenic ★ same residue
PTEN p.Ser305= Benign ★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition
PTEN c.1027-1852A>G 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-ser305arg (accessed [today's date]).

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