Is TSC2 p.Phe757Ile (c.2269T>A) pathogenic?

TSC2 p.Phe757Ile (c.2269T>A) is classified Uncertain significance in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-08). AlphaMissense: ambiguous (0.3748); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Phe757Ile (c.2269T>A)?

TSC2 p.Phe757Ile (c.2269T>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Phe757Ile (c.2269T>A) in the general population?

TSC2 p.Phe757Ile (c.2269T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Phe757Ile (c.2269T>A)?

AlphaMissense predicts ambiguous (score 0.3748) — an in-silico prediction, not a clinical call.

TSC2 p.Phe757Ile

c.2269T>A · rs2543764591 · VCV2449968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3748 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3748	ambiguous
REVEL	0.672	pathogenic-leaning
SaProt	LLR -9.47	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	25.9	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: TSC2
Protein: p.Phe757Ile
Coding: c.2269T>A
MANE Select: NM_000548
dbSNP: rs2543764591
Type: single nucleotide variant
Location: chr16:2072897 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TSC2 p.Phe757= Benign/Likely benign ★★ same residue
TSC2 p.Phe757Ser Uncertain significance ★ ⚠ same residue
TSC2 p.Phe757Tyr Uncertain significance ★ same residue
TSC2 p.Phe757Leu Uncertain significance ★ ⚠ same residue
TSC2 c.1443+2T>C Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1443+5G>C Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1599+1G>A Pathogenic ★★ same condition
TSC2 c.1716+1G>A Pathogenic/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/tsc2-p-phe757ile (accessed [today's date]).

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