Is PTEN p.Cys124Arg (c.370T>C) pathogenic?

PTEN p.Cys124Arg (c.370T>C) is classified Pathogenic in PTEN (ClinVar, Expert panel, 7 submitters; last evaluated 2019-06-25). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Cys124Arg (c.370T>C)?

PTEN p.Cys124Arg (c.370T>C) is associated with PTEN hamartoma tumor syndrome, gastric cancer, Cowden syndrome 1 (ClinVar).

How common is PTEN p.Cys124Arg (c.370T>C) in the general population?

PTEN p.Cys124Arg (c.370T>C) 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.Cys124Arg (c.370T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

PTEN p.Cys124Arg

c.370T>C · rs121909223 · VCV7817

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

Pathogenic for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):

PM2 PS4_Supporting PM6_Strong PS3 PM1 PP2

Curation rationale (ClinGen, verbatim)

PTEN c.370T>C (p.Cys124Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 29706350) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor SCV000568254.4) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000568254.4)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -14.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	33.0	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.Cys124Arg
Coding: c.370T>C
MANE Select: NM_000314
dbSNP: rs121909223
Type: single nucleotide variant
Location: chr10:87933129 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 124: the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1); a UniProt-annotated variant site (in cws1; phosphatase-dead protein with neither lipid nor protein phosphatase activity; loss of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity); an active site

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: gastric cancer Cowden syndrome 1 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.Cys124Gly Pathogenic ★★ same residue
PTEN p.Cys124Ser Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Cys124Trp Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Cys124Tyr Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Cys124Phe Pathogenic ★ same residue
PTEN p.Cys124fs Pathogenic 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-cys124arg (accessed [today's date]).

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