Is TSC1 p.Arg706Pro (c.2117G>C) pathogenic?

TSC1 p.Arg706Pro (c.2117G>C) is classified Uncertain significance in TSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-15). AlphaMissense: likely pathogenic (0.9957); Absent from gnomAD v4.1; Associated with tuberous sclerosis 1.

What condition is associated with TSC1 p.Arg706Pro (c.2117G>C)?

TSC1 p.Arg706Pro (c.2117G>C) is associated with tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Arg706Pro (c.2117G>C) in the general population?

TSC1 p.Arg706Pro (c.2117G>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 TSC1 p.Arg706Pro (c.2117G>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

TSC1 p.Arg706Pro

c.2117G>C · rs1588304158 · VCV1012028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 1

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic · top 1% in TSC1
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -15.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: TSC1
Protein: p.Arg706Pro
Coding: c.2117G>C
MANE Select: NM_000368
dbSNP: rs1588304158
Type: single nucleotide variant
Location: chr9:132903742 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 706: the 'mediates interaction with wdr45b' region; an α-helix; a UniProt-annotated variant site (in tsc1)

Full TSC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis 1 — 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

TSC1 p.Arg706Cys Uncertain significance ★★ ⚠ same residue
TSC1 p.Arg706Ser Uncertain significance ★★ ⚠ same residue
TSC1 p.Arg706= Likely benign ★★ same residue
TSC1 p.Arg706His Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1029+1G>C Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.107-1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1141+1G>A 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/tsc1-p-arg706pro (accessed [today's date]).

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