Is PTEN p.Arg335Ter (c.1003C>T) pathogenic?

PTEN p.Arg335Ter (c.1003C>T) is classified Pathogenic in PTEN (ClinVar, Expert panel, 46 submitters; last evaluated 2025-12-15). Very rare (popmax 0.00017%, nfe); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Arg335Ter (c.1003C>T)?

PTEN p.Arg335Ter (c.1003C>T) is associated with PTEN hamartoma tumor syndrome, congenital nervous system disorder, Cowden syndrome 1 (ClinVar).

How common is PTEN p.Arg335Ter (c.1003C>T) in the general population?

PTEN p.Arg335Ter (c.1003C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PTEN p.Arg335Ter

c.1003C>T · rs121909231 · VCV7833

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 46 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

PS2_VeryStrong PVS1 PM2_Supporting PS4 PP1

Curation rationale (ClinGen, verbatim)

PTEN c.1003C>T (p.Arg335Ter) meets criteria to be classified as Pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.8). PS4: Probands with phenotype specificity score of 4-15.5 PM2_Supporting: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 10353779) PS2_VS: One proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 40407579, PMID 22595938, PMID 30233642)

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (8 of 9, 23 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.1, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,498 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,168 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.Arg335Ter
Coding: c.1003C>T
MANE Select: NM_000314
dbSNP: rs121909231
Type: single nucleotide variant
Location: chr10:87961095 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 335: a β-strand; 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

PTEN hamartoma tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital nervous system disorder Cowden syndrome 1 prostate cancer macrocephaly-autism syndrome familial meningioma glioma susceptibility 2 hereditary neoplastic syndrome Cowden disease hereditary breast carcinoma Proteus-like syndrome ovarian neoplasm

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Arg335Gln Uncertain significance ★★★ ⚠ same residue
PTEN p.Arg335= Conflicting classifications of pathogenicity ★ same residue
PTEN p.Arg335Leu Uncertain significance ★ ⚠ same residue
PTEN p.Arg335Pro Uncertain significance ★ ⚠ same residue
PTEN p.Arg335fs Likely pathogenic ★ same residue
PTEN p.Arg335_Asn340del Uncertain significance ★ 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-arg335ter (accessed [today's date]).

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