Is TSC1 p.Pro349= (c.1047A>G) pathogenic?

TSC1 p.Pro349= (c.1047A>G) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.019%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro349= (c.1047A>G)?

TSC1 p.Pro349= (c.1047A>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Pro349= (c.1047A>G) in the general population?

TSC1 p.Pro349= (c.1047A>G) is ultra-rare (popmax 0.019%, nfe) (gnomAD).

TSC1 p.Pro349=

c.1047A>G · rs118203492 · VCV48736

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, 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 -6.8	GERP -2.7
Overall
CADD	3.789	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% European (non-Finnish) · 224/1,179,978 alleles

Filtering AF 0.0169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0144% 232/1,614,004 alleles · ultra-rare exomes 223/1,461,830 · genomes 9/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.019%	5,268
Remaining individualsnot grpmax-eligible	0.0096%	10,414
African / African-American	0.00267%	37,461

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.Pro349=
Coding: c.1047A>G
MANE Select: NM_000368
dbSNP: rs118203492
Type: single nucleotide variant
Location: chr9:132911096 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 349: 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 isolated focal cortical dysplasia type II

Similar variants

TSC1 p.Pro349Ala Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro349Gln Uncertain significance ★ ⚠ same residue
TSC1 p.Pro349Leu Uncertain significance ★ ⚠ same residue
TSC1 p.Pro349Ser 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

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-pro349 (accessed [today's date]).

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