Is PTEN p.Asp375Gly (c.1124A>G) pathogenic?

PTEN p.Asp375Gly (c.1124A>G) is classified Uncertain significance in PTEN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-20). AlphaMissense: likely pathogenic (0.7452); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Asp375Gly (c.1124A>G)?

PTEN p.Asp375Gly (c.1124A>G) is associated with PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Asp375Gly (c.1124A>G) in the general population?

PTEN p.Asp375Gly (c.1124A>G) is absent from gnomAD v4.1 (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.Asp375Gly (c.1124A>G)?

AlphaMissense predicts likely pathogenic (score 0.7452) — an in-silico prediction, not a clinical call.

PTEN p.Asp375Gly

c.1124A>G · rs1589669344 · VCV651164

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7452 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PTEN hamartoma tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.7452	likely pathogenic
REVEL	0.572	indeterminate
SaProt	LLR -7.25	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 2.9, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 115 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	26.4	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

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.Asp375Gly
Coding: c.1124A>G
MANE Select: NM_000314
dbSNP: rs1589669344
Type: single nucleotide variant
Location: chr10:87965384 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 375: 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

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Asp375Asn Uncertain significance ★ ⚠ same residue
PTEN p.Asp375fs Pathogenic ★ same residue
PTEN p.Asp375= Benign/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
PTEN c.165-1G>C 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-asp375gly (accessed [today's date]).

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