Is TSC2 p.Ser1269Pro (c.3805T>C) pathogenic?

TSC2 p.Ser1269Pro (c.3805T>C) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-18). AlphaMissense: likely benign (0.1384); Very rare (popmax 0.000169%, nfe); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Ser1269Pro (c.3805T>C)?

TSC2 p.Ser1269Pro (c.3805T>C) is associated with tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ser1269Pro (c.3805T>C) in the general population?

TSC2 p.Ser1269Pro (c.3805T>C) is very rare (popmax 0.000169%, nfe) (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 TSC2 p.Ser1269Pro (c.3805T>C)?

AlphaMissense predicts likely benign (score 0.1384) — an in-silico prediction, not a clinical call.

TSC2 p.Ser1269Pro

c.3805T>C · rs991523072 · VCV942998

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.1384	likely benign
REVEL	0.53	indeterminate
SaProt	LLR -9.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.68, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,964 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,336 alleles · very rare

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.Ser1269Pro
Coding: c.3805T>C
MANE Select: NM_000548
dbSNP: rs991523072
Type: single nucleotide variant
Location: chr16:2081789 (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

tuberous sclerosis 2 — 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

TSC2 p.Ser1269= Benign/Likely benign ★★ same residue
TSC2 p.Ser1269Cys Uncertain significance ★ ⚠ same residue
TSC2 p.Ser1269Phe 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-ser1269pro (accessed [today's date]).

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