Is TSC1 p.Arg709Ser (c.2127G>C) pathogenic?

TSC1 p.Arg709Ser (c.2127G>C) is classified Uncertain significance in TSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-16). AlphaMissense: likely pathogenic (0.9806); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Arg709Ser (c.2127G>C)?

TSC1 p.Arg709Ser (c.2127G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Arg709Ser (c.2127G>C) in the general population?

TSC1 p.Arg709Ser (c.2127G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC1 p.Arg709Ser (c.2127G>C)?

AlphaMissense predicts likely pathogenic (score 0.9806) — an in-silico prediction, not a clinical call.

TSC1 p.Arg709Ser

c.2127G>C · rs2131765779 · VCV1786339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9806 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9806	likely pathogenic · top 3% in TSC1
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	23.7	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: TSC1
Protein: p.Arg709Ser
Coding: c.2127G>C
MANE Select: NM_000368
dbSNP: rs2131765779
Type: single nucleotide variant
Location: chr9:132903732 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 709: 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TSC1 p.Arg709= Benign/Likely benign ★★ same residue
TSC1 p.Arg709Lys Uncertain significance ★ ⚠ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1997+2T>G Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1998-1G>T Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.2042-5A>G Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.2208+2T>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.2626-2A>C 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/tsc1-p-arg709ser (accessed [today's date]).

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