Is TSC1 p.Arg692Pro (c.2075G>C) pathogenic?

TSC1 p.Arg692Pro (c.2075G>C) is classified Uncertain significance in TSC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-22). AlphaMissense: likely pathogenic (0.923); Very rare (popmax 0.00223%, eas); Associated with tuberous sclerosis 1.

What condition is associated with TSC1 p.Arg692Pro (c.2075G>C)?

TSC1 p.Arg692Pro (c.2075G>C) is associated with tuberous sclerosis 1, hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Arg692Pro (c.2075G>C) in the general population?

TSC1 p.Arg692Pro (c.2075G>C) is very rare (popmax 0.00223%, eas) (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.Arg692Pro (c.2075G>C)?

AlphaMissense predicts likely pathogenic (score 0.923) — an in-silico prediction, not a clinical call.

TSC1 p.Arg692Pro

c.2075G>C · rs199755731 · VCV846317

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 1

Computational evidence

Protein change
AlphaMissense	0.923	likely pathogenic · top 8% in TSC1
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -10.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	28.5	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

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,940 alleles · very rare exomes 3/1,461,704 · genomes 0/152,236 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
European (non-Finnish)	0.000169%	590,016

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.Arg692Pro
Coding: c.2075G>C
MANE Select: NM_000368
dbSNP: rs199755731
Type: single nucleotide variant
Location: chr9:132903784 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 692: 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

Also linked: 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.Arg692Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Arg692Leu Uncertain significance ★ ⚠ same residue
TSC1 p.Arg692= Likely benign ★ same residue
TSC1 p.Arg692Ter Pathogenic ★ 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-arg692pro (accessed [today's date]).

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