Is PTEN p.Pro248fs (c.741dup) pathogenic?

PTEN p.Pro248fs (c.741dup) is classified Pathogenic in PTEN (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-07). Very rare (popmax 6.84e-05%); Associated with macrocephaly-autism syndrome.

What condition is associated with PTEN p.Pro248fs (c.741dup)?

PTEN p.Pro248fs (c.741dup) is associated with macrocephaly-autism syndrome, Cowden syndrome 1, prostate cancer (ClinVar).

How common is PTEN p.Pro248fs (c.741dup) in the general population?

PTEN p.Pro248fs (c.741dup) is very rare (popmax 6.84e-05%) (gnomAD).

PTEN p.Pro248fs

Q: How is Macrocephaly-intellectual disability-autism syndrome inherited?

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

c.741dup · rs587782341 · VCV142259

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

macrocephaly-autism syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,808 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.Pro248fs
Coding: c.741dup
MANE Select: NM_000314
dbSNP: rs587782341
Type: Duplication
Location: chr10:87957958 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 248: 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

macrocephaly-autism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cowden syndrome 1 prostate cancer familial meningioma glioma susceptibility 2 hereditary neoplastic syndrome PTEN hamartoma tumor syndrome

For Macrocephaly-intellectual disability-autism syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PTEN p.Pro248Ser Uncertain significance ★★ ⚠ same residue
PTEN p.Pro248Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Pro248Leu Uncertain significance ★ ⚠ same residue
PTEN p.Pro248= Likely benign ★ same residue
PTEN p.Arg172fs Pathogenic ★★★ same condition
PTEN c.209+2dup Uncertain significance ★★★ same condition
PTEN p.Lys102dup Uncertain significance ★★★ same condition
PTEN c.254-30dup Benign ★★★ 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-pro248fs (accessed [today's date]).

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