Is TSC2 p.Lys1663Asn (c.4989G>T) pathogenic?

TSC2 p.Lys1663Asn (c.4989G>T) is classified Likely pathogenic in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-20). AlphaMissense: likely pathogenic (0.9344); Absent from gnomAD v4.1.

How common is TSC2 p.Lys1663Asn (c.4989G>T) in the general population?

TSC2 p.Lys1663Asn (c.4989G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Lys1663Asn (c.4989G>T)?

AlphaMissense predicts likely pathogenic (score 0.9344) — an in-silico prediction, not a clinical call.

TSC2 p.Lys1663Asn

c.4989G>T · VCV4070736

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9344 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9344	likely pathogenic ✓ concordant with ClinVar
REVEL	0.689	pathogenic-leaning
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.60	donor gain · deltas
Pangolin	Δ0.50	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP -1.9, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,785 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Lys1663Asn
Coding: c.4989G>T
MANE Select: NM_000548
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

Similar variants

TSC2 p.Lys1663= Uncertain significance ★★ same residue
TSC2 p.Lys1663Thr Uncertain significance ★ ⚠ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same type
TSC2 c.1258-2A>G Pathogenic ★★ same type
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same type
TSC2 c.1361+1G>T Pathogenic/Likely pathogenic ★★ same type
TSC2 c.1362-1G>A Pathogenic ★★ same type
TSC2 c.138+2T>C Pathogenic ★★ same type

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-lys1663asn (accessed [today's date]).

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