Is TSC2 p.Ser1281= (c.3843C>T) pathogenic?

TSC2 p.Ser1281= (c.3843C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-20). Very rare (popmax 0.00329%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ser1281= (c.3843C>T)?

TSC2 p.Ser1281= (c.3843C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ser1281= (c.3843C>T) in the general population?

TSC2 p.Ser1281= (c.3843C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

TSC2 p.Ser1281=

c.3843C>T · rs1223688571 · VCV766864

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

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 4.7	GERP 1.6, phastCons 1
Overall
CADD	11.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,092 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000868% 14/1,612,382 alleles · very rare exomes 13/1,460,170 · genomes 1/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,364
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	0.000847%	118,001

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: TSC2
Protein: p.Ser1281=
Coding: c.3843C>T
MANE Select: NM_000548
dbSNP: rs1223688571
Type: single nucleotide variant
Location: chr16:2082464 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB

Full TSC2 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 2

Similar variants

TSC2 p.Ser1281Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser1281Phe Uncertain significance ★ ⚠ same residue
TSC2 p.Ser1281Tyr Uncertain significance ★ ⚠ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G Pathogenic ★★ same condition
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1361+1G>T Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1362-1G>A 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/tsc2-p-ser1281 (accessed [today's date]).

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