Is TSC1 p.Pro641Ser (c.1921C>T) pathogenic?

TSC1 p.Pro641Ser (c.1921C>T) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0735); Ultra-rare (popmax 0.0423%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro641Ser (c.1921C>T)?

TSC1 p.Pro641Ser (c.1921C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Pro641Ser (c.1921C>T) in the general population?

TSC1 p.Pro641Ser (c.1921C>T) is ultra-rare (popmax 0.0423%, eas) (gnomAD).

What do computational predictors say about TSC1 p.Pro641Ser (c.1921C>T)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

TSC1 p.Pro641Ser

c.1921C>T · rs374222196 · VCV135364

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -5.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	16.34	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 0.0423% East Asian · 19/44,896 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00496% 80/1,614,074 alleles · ultra-rare exomes 70/1,461,894 · genomes 10/152,180 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0864%	1,157
East Asiangrpmax	0.0423%	2,363
Admixed American	0.00833%	11,999
European (non-Finnish)	0.000169%	590,019

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro641Ser
Coding: c.1921C>T
MANE Select: NM_000368
dbSNP: rs374222196
Type: single nucleotide variant
Location: chr9:132905657 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 641: 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

Similar variants

TSC1 p.Pro641Leu Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro641His Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro641ser (accessed [today's date]).

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