Is TSC2 p.Ser1364Phe (c.4091C>T) pathogenic?

TSC2 p.Ser1364Phe (c.4091C>T) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-17). AlphaMissense: likely benign (0.0949); Very rare (popmax 0.00263%, nfe); Associated with tuberous sclerosis.

What condition is associated with TSC2 p.Ser1364Phe (c.4091C>T)?

TSC2 p.Ser1364Phe (c.4091C>T) is associated with tuberous sclerosis, tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ser1364Phe (c.4091C>T) in the general population?

TSC2 p.Ser1364Phe (c.4091C>T) is very rare (popmax 0.00263%, 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.Ser1364Phe (c.4091C>T)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

TSC2 p.Ser1364Phe

c.4091C>T · rs1245757559 · VCV2454061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

tuberous sclerosis

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -8.66	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 3.2	GERP 0.55, phastCons 0.13
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	17.86	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 0.00263% European (non-Finnish) · 31/1,179,974 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00198% 32/1,612,652 alleles · very rare exomes 31/1,460,418 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00263%	38,064
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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.Ser1364Phe
Coding: c.4091C>T
MANE Select: NM_000548
dbSNP: rs1245757559
Type: single nucleotide variant
Location: chr16:2084313 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1364: a modified residue (phosphoserine); the 'disordered' region

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis 2 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.Ser1364Cys Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser1364Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ser1364Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ser1364= Likely benign ★ same residue
TSC2 p.Ser1364Val Likely benign ★★ 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

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-ser1364phe (accessed [today's date]).

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