Is TSC2 p.Pro1508fs (c.4522_4523insAA) pathogenic?

TSC2 p.Pro1508fs (c.45224523insAA) is classified Pathogenic in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-30). Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1508fs (c.4522_4523insAA)?

TSC2 p.Pro1508fs (c.4522_4523insAA) is associated with hereditary neoplastic syndrome (ClinVar).

TSC2 p.Pro1508fs

c.4522_4523insAA · VCV3462601

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

hereditary neoplastic 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 35 of 42
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1

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

Variant & gene context

Gene: TSC2
Protein: p.Pro1508fs
Coding: c.4522_4523insAA
MANE Select: NM_000548
Type: Insertion
Location: chr16:2084979 (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.Pro1508Arg Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1508del Uncertain significance ★★ same residue
TSC2 p.Pro1508Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1508Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1508Ala Uncertain significance ★ same residue
TSC2 p.Pro1508= Likely benign ★★ same residue
TSC2 p.Glu1021fs Pathogenic ★ same condition
TSC2 p.Arg1245_Asp1246insVal 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-pro1508fs (accessed [today's date]).

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