Is TSC2 p.Arg1122Pro (c.3365G>C) pathogenic?

TSC2 p.Arg1122Pro (c.3365G>C) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-18). AlphaMissense: likely benign (0.1554); Very rare (popmax 0.00224%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Arg1122Pro (c.3365G>C)?

TSC2 p.Arg1122Pro (c.3365G>C) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Arg1122Pro (c.3365G>C) in the general population?

TSC2 p.Arg1122Pro (c.3365G>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about TSC2 p.Arg1122Pro (c.3365G>C)?

AlphaMissense predicts likely benign (score 0.1554) — an in-silico prediction, not a clinical call.

TSC2 p.Arg1122Pro

c.3365G>C · rs369536711 · VCV451736

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1554	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -5.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -3.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	21.9	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 0.00224% East Asian · 1/44,654 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000311% 5/1,607,174 alleles · very rare exomes 5/1,454,848 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,654
European (non-Finnish)	0.00034%	294,424

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.Arg1122Pro
Coding: c.3365G>C
MANE Select: NM_000548
dbSNP: rs369536711
Type: single nucleotide variant
Location: chr16:2079637 (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.Arg1122= Conflicting classifications of pathogenicity ★ same residue
TSC2 p.Arg1122His 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-arg1122pro (accessed [today's date]).

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