Is TSC1 p.Ser444= (c.1332A>G) pathogenic?

TSC1 p.Ser444= (c.1332A>G) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-02). Very rare (popmax 0.005%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Ser444= (c.1332A>G)?

TSC1 p.Ser444= (c.1332A>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Ser444= (c.1332A>G) in the general population?

TSC1 p.Ser444= (c.1332A>G) is very rare (popmax 0.005%, nfe) (gnomAD).

TSC1 p.Ser444=

c.1332A>G · rs773003016 · VCV207632

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, 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 1.8	GERP 1.8, phastCons 0.99
Overall
CADD	17.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% European (non-Finnish) · 59/1,179,402 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00409% 66/1,613,408 alleles · very rare exomes 60/1,461,160 · genomes 6/152,248 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,615
European (non-Finnish)grpmax	0.005%	19,990
South Asian	0.0022%	45,540
African / African-American	0.00133%	74,944

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.Ser444=
Coding: c.1332A>G
MANE Select: NM_000368
dbSNP: rs773003016
Type: single nucleotide variant
Location: chr9:132907302 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 444: the 'mediates interaction with wdr45b' region; the 'disordered' 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.Ser444Leu Uncertain significance ★★ ⚠ same residue
TSC1 p.Ser444Thr 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
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-ser444 (accessed [today's date]).

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