Is TSC2 p.Lys1663= (c.4989G>A) pathogenic?

TSC2 p.Lys1663= (c.4989G>A) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-11). Very rare (popmax 0.000257%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Lys1663= (c.4989G>A)?

TSC2 p.Lys1663= (c.4989G>A) is associated with hereditary neoplastic syndrome, isolated focal cortical dysplasia type II, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Lys1663= (c.4989G>A) in the general population?

TSC2 p.Lys1663= (c.4989G>A) is very rare (popmax 0.000257%, nfe) (gnomAD).

TSC2 p.Lys1663=

c.4989G>A · rs1567124948 · VCV571995

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000257%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.57	donor gain · deltas
Pangolin	Δ0.37	gain · loss 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP -1.9, phastCons 1
Overall
CADD	17.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000257% European (non-Finnish) · 3/1,165,976 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00021% 3/1,430,930 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TSC2
Protein: p.Lys1663=
Coding: c.4989G>A
MANE Select: NM_000548
dbSNP: rs1567124948
Type: single nucleotide variant
Location: chr16:2086871 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1663: the rap-gap domain

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: isolated focal cortical dysplasia type II tuberous sclerosis 2

Similar variants

TSC2 p.Lys1663Thr Uncertain significance ★ ⚠ same residue
TSC2 p.Lys1663Asn Likely pathogenic ★ ⚠ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G Pathogenic ★★ same condition
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1361+1G>T 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-lys1663 (accessed [today's date]).

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