Is TSC1 p.Ala726Val (c.2177C>T) pathogenic?

TSC1 p.Ala726Val (c.2177C>T) is classified Uncertain significance in TSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-20). AlphaMissense: likely benign (0.1311); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Ala726Val (c.2177C>T)?

TSC1 p.Ala726Val (c.2177C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Ala726Val (c.2177C>T) in the general population?

TSC1 p.Ala726Val (c.2177C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC1 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

TSC1 p.Ala726Val

c.2177C>T · rs118203655 · VCV1787199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Ala726Val
Coding: c.2177C>T
MANE Select: NM_000368
dbSNP: rs118203655
Type: single nucleotide variant
Location: chr9:132903682 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 726: 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.Ala726= Benign/Likely benign ★★ same residue
TSC1 p.Ala726Pro 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-ala726val (accessed [today's date]).

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