Is PTEN p.Leu98Pro (c.293T>C) pathogenic?

PTEN p.Leu98Pro (c.293T>C) is classified Pathogenic/Likely pathogenic in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1; Associated with macrocephaly-autism syndrome.

What condition is associated with PTEN p.Leu98Pro (c.293T>C)?

PTEN p.Leu98Pro (c.293T>C) is associated with macrocephaly-autism syndrome (ClinVar).

How common is PTEN p.Leu98Pro (c.293T>C) in the general population?

PTEN p.Leu98Pro (c.293T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTEN p.Leu98Pro (c.293T>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

PTEN p.Leu98Pro

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

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

c.293T>C · VCV3767590

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

macrocephaly-autism syndrome

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic ✓ concordant with ClinVar
REVEL	0.912	moderately pathogenic-leaning
SaProt	LLR -12.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	31.0	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.Leu98Pro
Coding: c.293T>C
MANE Select: NM_000314
Type: single nucleotide variant
Location: chr10:87933052 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 98: an α-helix; the phosphatase 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

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

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PTEN p.Leu98Arg Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Leu98= Benign/Likely benign ★★ same residue
PTEN p.Leu98Val Uncertain significance ★ ⚠ same residue
PTEN c.634+2T>C Pathogenic ★★★ same condition
PTEN c.634+5G>A Pathogenic ★★★ same condition
PTEN p.Arg173Cys Pathogenic ★★★ same condition
PTEN p.Arg335Ter Pathogenic ★★★ same condition
PTEN p.Asp107Val 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-leu98pro (accessed [today's date]).

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