Is TSC2 p.Phe1241= (c.3723C>T) pathogenic?

TSC2 p.Phe1241= (c.3723C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-01-31). Rare (popmax 0.27%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Phe1241= (c.3723C>T)?

TSC2 p.Phe1241= (c.3723C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Phe1241= (c.3723C>T) in the general population?

TSC2 p.Phe1241= (c.3723C>T) is rare (popmax 0.27%, afr) (gnomAD).

TSC2 p.Phe1241=

c.3723C>T · rs45486193 · VCV49271

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

rare (popmax 0.27%, afr)

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 0.53	GERP 0.41, phastCons 1
Overall
CADD	8.944	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.27% African / African-American · 203/75,064 alleles

Filtering AF 0.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.228%

Overall 0.0138% 222/1,612,974 alleles · rare exomes 108/1,460,606 · genomes 114/152,368 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.27%	370
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.016%	6,249
Admixed American	0.00666%	15,009
European (non-Finnish)	0.000339%	295,005

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.Phe1241=
Coding: c.3723C>T
MANE Select: NM_000548
dbSNP: rs45486193
Type: single nucleotide variant
Location: chr16:2081707 (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 tuberous sclerosis 2

Similar variants

TSC2 p.Phe1241Leu 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
TSC2 c.138+2T>C Pathogenic ★★ same condition
TSC2 c.138+5G>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-phe1241 (accessed [today's date]).

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