Is TSC1 p.Pro419= (c.1257C>G) pathogenic?

TSC1 p.Pro419= (c.1257C>G) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-10-05). Ultra-rare (popmax 0.0164%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro419= (c.1257C>G)?

TSC1 p.Pro419= (c.1257C>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Pro419= (c.1257C>G) in the general population?

TSC1 p.Pro419= (c.1257C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

TSC1 p.Pro419=

c.1257C>G · rs369642207 · VCV237698

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.041	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -1.1, phastCons 0.99
Overall
CADD	7.374	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00254% 41/1,613,910 alleles · ultra-rare exomes 38/1,461,740 · genomes 3/152,170 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00305%	32,779
East Asian	0.00223%	44,890
South Asian	0.0022%	45,546
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro419=
Coding: c.1257C>G
MANE Select: NM_000368
dbSNP: rs369642207
Type: single nucleotide variant
Location: chr9:132910577 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 419: 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis tuberous sclerosis 1 lymphangioleiomyomatosis isolated focal cortical dysplasia type II

Similar variants

TSC1 p.Pro419Leu Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro419Thr Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro419Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Pro419Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Pro419His Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Pro419Ser Uncertain significance ★ ⚠ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1029+1G>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-pro419 (accessed [today's date]).

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