Is TSC1 p.Arg22Pro (c.65G>C) pathogenic?

TSC1 p.Arg22Pro (c.65G>C) is classified Uncertain significance in TSC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: ambiguous (0.5483); Very rare (popmax 6.84e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Arg22Pro (c.65G>C)?

TSC1 p.Arg22Pro (c.65G>C) is associated with hereditary neoplastic syndrome, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Arg22Pro (c.65G>C) in the general population?

TSC1 p.Arg22Pro (c.65G>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about TSC1 p.Arg22Pro (c.65G>C)?

AlphaMissense predicts ambiguous (score 0.5483) — an in-silico prediction, not a clinical call.

TSC1 p.Arg22Pro

c.65G>C · rs141736779 · VCV466151

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5483 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5483	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -13.27	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.068, phastCons 0.81
Regional constraint	o/e 0.76	unconstrained · MANE · 23 kb · p 5.3e-09 · regional, not allelic
Overall
CADD	18.01	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 6.84e-05%

Overall 6.84e-05% 1/1,461,862 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.Arg22Pro
Coding: c.65G>C
MANE Select: NM_000368
dbSNP: rs141736779
Type: single nucleotide variant
Location: chr9:132928808 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 22: a UniProt-annotated variant site (in fcord2; somatic mutation; decreased interaction with tsc2; decreased function in negative regulation of tor signaling); an α-helix

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

Also linked: tuberous sclerosis 1

Similar variants

TSC1 p.Arg22Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Arg22Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Arg22= Likely benign ★ 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

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-arg22pro (accessed [today's date]).

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