Is TSC2 p.Trp1430Ter (c.4289G>A) pathogenic?

TSC2 p.Trp1430Ter (c.4289G>A) is classified Likely pathogenic in TSC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-18). Absent from gnomAD v4.1; Associated with isolated focal cortical dysplasia type II.

What condition is associated with TSC2 p.Trp1430Ter (c.4289G>A)?

TSC2 p.Trp1430Ter (c.4289G>A) is associated with isolated focal cortical dysplasia type II, tuberous sclerosis (ClinVar).

How common is TSC2 p.Trp1430Ter (c.4289G>A) in the general population?

TSC2 p.Trp1430Ter (c.4289G>A) is absent from gnomAD v4.1 (gnomAD).

TSC2 p.Trp1430Ter

c.4289G>A · rs45507198 · VCV49290

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

isolated focal cortical dysplasia type II

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 34 of 42
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.8, phastCons 1
Overall
CADD	44.0	PHRED · no single calibrated threshold — expert panels disagree

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

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.Trp1430Ter
Coding: c.4289G>A
MANE Select: NM_000548
dbSNP: rs45507198
Type: single nucleotide variant
Location: chr16:2084511 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1430: the 'disordered' region

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

Disease context

isolated focal cortical dysplasia type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis

For Isolated focal cortical dysplasia (Orphanet):

Onset: All ages

Similar variants

TSC2 p.Trp1430Arg Uncertain significance ★★ ⚠ same residue
TSC2 p.Trp1430Cys Uncertain significance ★ ⚠ same residue
TSC2 p.Trp1430Leu Uncertain significance ★ ⚠ same residue
TSC2 p.Trp1430Ser Uncertain significance ★ ⚠ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1362-1G>A Pathogenic ★★ same condition
TSC2 c.138+2T>C 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-trp1430ter (accessed [today's date]).

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