Is TSC2 p.Arg1122= (c.3366T>C) pathogenic?

TSC2 p.Arg1122= (c.3366T>C) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0174%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Arg1122= (c.3366T>C)?

TSC2 p.Arg1122= (c.3366T>C) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Arg1122= (c.3366T>C) in the general population?

TSC2 p.Arg1122= (c.3366T>C) is ultra-rare (popmax 0.0174%, mid) (gnomAD).

TSC2 p.Arg1122=

c.3366T>C · rs778352969 · VCV281341

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -13	GERP -3.9
Overall
CADD	0.429	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0174% Middle Eastern · 1/5,750 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000373% 6/1,607,248 alleles · ultra-rare exomes 5/1,455,096 · genomes 1/152,152 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0174%	5,750
Admixed American	0.00169%	59,296
Remaining individualsnot grpmax-eligible	0.00161%	62,086
European (non-Finnish)	0.000255%	392,610

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.Arg1122=
Coding: c.3366T>C
MANE Select: NM_000548
dbSNP: rs778352969
Type: single nucleotide variant
Location: chr16:2079638 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1122: the 'disordered' 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.Arg1122Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg1122Cys Benign/Likely benign ★★ same residue
TSC2 p.Arg1122His Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Arg1122Pro Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg1122 (accessed [today's date]).

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