Is PTEN p.Asp368= (c.1104T>C) pathogenic?

PTEN p.Asp368= (c.1104T>C) is classified Likely benign in PTEN (ClinVar, Expert panel, 19 submitters; last evaluated 2016-09-14). Rare (popmax 0.538%, afr); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Asp368= (c.1104T>C)?

PTEN p.Asp368= (c.1104T>C) is associated with PTEN hamartoma tumor syndrome, breast cancer, Cowden syndrome 1 (ClinVar).

How common is PTEN p.Asp368= (c.1104T>C) in the general population?

PTEN p.Asp368= (c.1104T>C) is rare (popmax 0.538%, afr) (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

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

PTEN p.Asp368=

c.1104T>C · rs35979531 · VCV138835

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

gnomAD v4.1

Rare

rare (popmax 0.538%, afr)

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

BS1 BP7 BP4

Curation rationale (ClinGen, verbatim)

PTEN c.1104T>C (p.D368=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1: Allele frequency of 0.0057 (0.57%, 130/22,966 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact. BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted.

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.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.80 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.049	GERP -1.1, phastCons 0.96
Overall
CADD	7.346	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.538% African / African-American · 403/74,932 alleles

Filtering AF 0.494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.477%

Overall 0.0304% 489/1,609,228 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.538%	186
Admixed American	0.0503%	1,986
Remaining individualsnot grpmax-eligible	0.0402%	2,489
Middle Eastern	0.033%	3,026
South Asian	0.011%	9,054
European (non-Finnish)	0.00161%	61,951

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.Asp368=
Coding: c.1104T>C
MANE Select: NM_000314
dbSNP: rs35979531
Type: single nucleotide variant
Location: chr10:87965364 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 368: 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: breast 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.Asp368Glu Uncertain significance ★★ ⚠ same residue
PTEN p.Asp368Val Uncertain significance ★ ⚠ same residue
PTEN p.Asp368fs Likely pathogenic ★ 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-asp368 (accessed [today's date]).

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