Is TSC2 p.Arg1706Pro (c.5117G>C) pathogenic?

TSC2 p.Arg1706Pro (c.5117G>C) is classified Uncertain significance in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-30). AlphaMissense: ambiguous (0.4783); Absent from gnomAD v4.1; Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Arg1706Pro (c.5117G>C)?

TSC2 p.Arg1706Pro (c.5117G>C) is associated with tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Arg1706Pro (c.5117G>C) in the general population?

TSC2 p.Arg1706Pro (c.5117G>C) is absent from gnomAD v4.1 (gnomAD).

How is Tuberous sclerosis complex inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TSC2 p.Arg1706Pro (c.5117G>C)?

AlphaMissense predicts ambiguous (score 0.4783) — an in-silico prediction, not a clinical call.

TSC2 p.Arg1706Pro

c.5117G>C · VCV4802891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4783 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.4783	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -8.85	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.47, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,785 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	24.0	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.Arg1706Pro
Coding: c.5117G>C
MANE Select: NM_000548
Type: single nucleotide variant
Location: chr16:2088096 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1706: the rap-gap domain; a turn

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Tuberous sclerosis complex (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Taiwan, Province of China)

Similar variants

TSC2 p.Arg1706Gly Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg1706Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg1706Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Arg1706Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Arg1706_Asn1707del Uncertain significance ★ same residue
TSC2 p.Arg1706= Likely benign ★ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G 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-arg1706pro (accessed [today's date]).

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