Is TSC2 p.Phe453Ter (c.1358_1359delinsAA) pathogenic?

TSC2 p.Phe453Ter (c.13581359delinsAA) is classified Pathogenic in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-07-16). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Phe453Ter (c.1358_1359delinsAA)?

TSC2 p.Phe453Ter (c.1358_1359delinsAA) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Phe453Ter (c.1358_1359delinsAA) in the general population?

TSC2 p.Phe453Ter (c.1358_1359delinsAA) is no gnomAD frequency available for this variant (gnomAD).

TSC2 p.Phe453Ter

c.1358_1359delinsAA · rs2151165414 · VCV1397684

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary neoplastic syndrome

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	predicted	premature termination codon in exon 13 of 42
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TSC2
Protein: p.Phe453Ter
Coding: c.1358_1359delinsAA
MANE Select: NM_000548
dbSNP: rs2151165414
Type: Indel
Location: chr16:2062597 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 453: an α-helix

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

Also linked: tuberous sclerosis 2

Similar variants

TSC2 p.Phe453= Likely benign ★★ same residue
TSC2 p.Phe453Leu Uncertain significance ★ ⚠ same residue
TSC2 p.Val827fs Pathogenic ★★ same condition
TSC2 p.Ala675Leu Uncertain significance ★★ same condition
TSC2 p.Glu1107Met Uncertain significance ★★ same condition
TSC2 p.Glu1351Leu Uncertain significance ★★ same condition
TSC2 p.Glu393Leu Uncertain significance ★★ same condition
TSC2 p.Gly1664Ala Uncertain significance ★★ 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-phe453ter (accessed [today's date]).

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