Is TSC1 p.Pro169Ser (c.505C>T) pathogenic?

TSC1 p.Pro169Ser (c.505C>T) is classified Uncertain significance in TSC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1921); Absent from gnomAD v4.1; Associated with tuberous sclerosis 1.

What condition is associated with TSC1 p.Pro169Ser (c.505C>T)?

TSC1 p.Pro169Ser (c.505C>T) is associated with tuberous sclerosis 1, hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Pro169Ser (c.505C>T) in the general population?

TSC1 p.Pro169Ser (c.505C>T) is absent from gnomAD v4.1 (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.Pro169Ser (c.505C>T)?

AlphaMissense predicts likely benign (score 0.1921) — an in-silico prediction, not a clinical call.

TSC1 p.Pro169Ser

c.505C>T · VCV4744105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1921 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 1

Computational evidence

Protein change
AlphaMissense	0.1921	likely benign
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -6.12	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 23 kb · p 5.3e-09 · regional, not allelic
Overall
CADD	27.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC1
Protein: p.Pro169Ser
Coding: c.505C>T
MANE Select: NM_000368
Type: single nucleotide variant
Location: chr9:132923351 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 169: 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.Pro169= Uncertain significance ★★ same residue
TSC1 p.Pro169Arg Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro169Gln 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

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-pro169ser (accessed [today's date]).

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