Is TSC1 p.Pro448Ser (c.1342C>T) pathogenic?

TSC1 p.Pro448Ser (c.1342C>T) is classified Benign/Likely benign in TSC1 (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0611); Low-frequency (popmax 1.22%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro448Ser (c.1342C>T)?

TSC1 p.Pro448Ser (c.1342C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, autism spectrum disorder (ClinVar).

How common is TSC1 p.Pro448Ser (c.1342C>T) in the general population?

TSC1 p.Pro448Ser (c.1342C>T) is low-frequency (popmax 1.22%, afr) (gnomAD).

What do computational predictors say about TSC1 p.Pro448Ser (c.1342C>T)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

TSC1 p.Pro448Ser

c.1342C>T · rs118203518 · VCV48770

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.22%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP -2.3
Regional constraint	o/e 0.76	unconstrained · MANE · 23 kb · p 5.3e-09 · regional, not allelic
Overall
CADD	7.768	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 1.22% African / African-American · 918/75,002 alleles

Filtering AF 1.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.13%

Overall 0.0658% 1,062/1,614,020 alleles · low-frequency exomes 536/1,461,774 · genomes 526/152,246 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.22%	82
Middle Eastern	0.149%	673
Remaining individualsnot grpmax-eligible	0.102%	977
Admixed American	0.0966%	1,035
South Asian	0.00439%	22,764
European (non-Finnish)	0.000763%	131,113

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.Pro448Ser
Coding: c.1342C>T
MANE Select: NM_000368
dbSNP: rs118203518
Type: single nucleotide variant
Location: chr9:132906827 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 448: the 'mediates interaction with wdr45b' region; the 'disordered' region; a UniProt-annotated variant site (in tsc1); a UniProt-annotated variant site (no effect on expression; no effect on subcellular localization; no effect on inhibition of torc1 signaling)

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 autism spectrum disorder tuberous sclerosis 1 isolated focal cortical dysplasia type II

Similar variants

TSC1 p.Pro448Leu Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro448= Benign/Likely benign ★★ same residue
TSC1 p.Pro448Thr 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-pro448ser (accessed [today's date]).

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