Is TSC1 p.Pro684Arg (c.2051C>G) pathogenic?

TSC1 p.Pro684Arg (c.2051C>G) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-05). AlphaMissense: ambiguous (0.536); Very rare (popmax 0.000254%, nfe); Associated with tuberous sclerosis 1.

What condition is associated with TSC1 p.Pro684Arg (c.2051C>G)?

TSC1 p.Pro684Arg (c.2051C>G) is associated with tuberous sclerosis 1, isolated focal cortical dysplasia type II, hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Pro684Arg (c.2051C>G) in the general population?

TSC1 p.Pro684Arg (c.2051C>G) is very rare (popmax 0.000254%, nfe) (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.Pro684Arg (c.2051C>G)?

AlphaMissense predicts ambiguous (score 0.536) — an in-silico prediction, not a clinical call.

TSC1 p.Pro684Arg

c.2051C>G · rs1845511359 · VCV843140

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

tuberous sclerosis 1

Computational evidence

Protein change
AlphaMissense	0.536	ambiguous
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -7.05	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	28.6	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 0.000254% European (non-Finnish) · 3/1,180,016 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,622 alleles · very rare

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: TSC1
Protein: p.Pro684Arg
Coding: c.2051C>G
MANE Select: NM_000368
dbSNP: rs1845511359
Type: single nucleotide variant
Location: chr9:132903808 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 684: the 'mediates interaction with wdr45b' region; 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

Also linked: isolated focal cortical dysplasia type II hereditary neoplastic syndrome

For Tuberous sclerosis complex (Orphanet):

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

Similar variants

TSC1 p.Pro684Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Pro684del Uncertain significance ★★ 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
TSC1 c.1264-1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1439-1G>A 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-pro684arg (accessed [today's date]).

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