Is TSC1 p.Pro399Ter (c.1195_1196delinsTG) pathogenic?

TSC1 p.Pro399Ter (c.11951196delinsTG) is classified Pathogenic in TSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-08). Absent from gnomAD; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro399Ter (c.1195_1196delinsTG)?

TSC1 p.Pro399Ter (c.1195_1196delinsTG) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Pro399Ter (c.1195_1196delinsTG) in the general population?

TSC1 p.Pro399Ter (c.1195_1196delinsTG) is absent from gnomAD (gnomAD).

TSC1 p.Pro399Ter

c.1195_1196delinsTG · rs2538834207 · VCV1745728

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

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 12 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.26	GERP -0.058, phastCons 0.005

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: TSC1
Protein: p.Pro399Ter
Coding: c.1195_1196delinsTG
MANE Select: NM_000368
dbSNP: rs2538834207
Type: Indel
Location: chr9:132910638 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 399: a UniProt-annotated variant site (in tsc1)

Full TSC1 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

TSC1 p.Pro399Ala Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro399Ser Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro399= Likely benign ★★ same residue
TSC1 p.Pro399Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Ala1026Phe Uncertain significance ★★ same condition
TSC1 p.Ala428Leu Uncertain significance ★★ same condition
TSC1 p.Gly1036Lys Uncertain significance ★★ same condition
TSC1 p.Gly38Asp 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/tsc1-p-pro399ter (accessed [today's date]).

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