Is TSC2 p.Ser716Phe (c.2147C>T) pathogenic?

TSC2 p.Ser716Phe (c.2147C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.4619); Very rare (popmax 0.00333%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ser716Phe (c.2147C>T)?

TSC2 p.Ser716Phe (c.2147C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ser716Phe (c.2147C>T) in the general population?

TSC2 p.Ser716Phe (c.2147C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TSC2 p.Ser716Phe (c.2147C>T)?

AlphaMissense predicts ambiguous (score 0.4619) — an in-silico prediction, not a clinical call.

TSC2 p.Ser716Phe

c.2147C>T · rs781153452 · VCV380717

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4619	ambiguous
REVEL	0.55	indeterminate
SaProt	LLR -0.47	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,614,006 alleles · very rare exomes 2/1,461,786 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,004
European (non-Finnish)	8.47e-05%	1,180,052

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.Ser716Phe
Coding: c.2147C>T
MANE Select: NM_000548
dbSNP: rs781153452
Type: single nucleotide variant
Location: chr16:2072290 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 716: an α-helix

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.Ser716Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser716= Benign/Likely benign ★★ same residue
TSC2 p.Ser716Tyr 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-ser716phe (accessed [today's date]).

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