Is TSC1 p.Pro67= (c.201A>G) pathogenic?

TSC1 p.Pro67= (c.201A>G) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0369%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro67= (c.201A>G)?

TSC1 p.Pro67= (c.201A>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Pro67= (c.201A>G) in the general population?

TSC1 p.Pro67= (c.201A>G) is ultra-rare (popmax 0.0369%, nfe) (gnomAD).

TSC1 p.Pro67=

c.201A>G · rs371555137 · VCV137729

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0369%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -3.2
Overall
CADD	5.949	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0369% European (non-Finnish) · 435/1,179,916 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0328%

Overall 0.0279% 450/1,613,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0369%	2,712
Remaining individualsnot grpmax-eligible	0.0192%	5,206
African / African-American	0.00267%	37,462
South Asian	0.0011%	91,012

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.Pro67=
Coding: c.201A>G
MANE Select: NM_000368
dbSNP: rs371555137
Type: single nucleotide variant
Location: chr9:132927210 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB

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 tuberous sclerosis 1

Similar variants

TSC1 p.Pro67Leu 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
TSC1 c.1997+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-pro67 (accessed [today's date]).

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