Is TSC2 p.Lys7Arg (c.20A>G) pathogenic?

TSC2 p.Lys7Arg (c.20A>G) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-16). AlphaMissense: likely benign (0.0743); Ultra-rare (popmax 0.0169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Lys7Arg (c.20A>G)?

TSC2 p.Lys7Arg (c.20A>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Lys7Arg (c.20A>G) in the general population?

TSC2 p.Lys7Arg (c.20A>G) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about TSC2 p.Lys7Arg (c.20A>G)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

TSC2 p.Lys7Arg

c.20A>G · rs137854215 · VCV49194

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	26.5	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

Grpmax group 0.0169% European (non-Finnish) · 199/1,180,040 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0142%

Overall 0.013% 210/1,613,846 alleles · ultra-rare exomes 189/1,461,664 · genomes 21/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0169%	5,930
East Asian	0.00668%	14,967
African / African-American	0.00534%	18,730
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Admixed American	0.00167%	59,990

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.Lys7Arg
Coding: c.20A>G
MANE Select: NM_000548
dbSNP: rs137854215
Type: single nucleotide variant
Location: chr16:2048635 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 7: the 'required for interaction with tsc1' region

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: tuberous sclerosis tuberous sclerosis 2

Similar variants

TSC2 p.Lys7Glu Uncertain significance ★ ⚠ same residue
TSC2 p.Lys7Thr Uncertain significance ★ ⚠ same residue
TSC2 p.Lys7fs 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

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-lys7arg (accessed [today's date]).

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