Is TSC2 p.Phe239Cys (c.716T>G) pathogenic?

TSC2 p.Phe239Cys (c.716T>G) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.8012); Ultra-rare (popmax 0.0812%, sas); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Phe239Cys (c.716T>G)?

TSC2 p.Phe239Cys (c.716T>G) is associated with tuberous sclerosis 2, tuberous sclerosis, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Phe239Cys (c.716T>G) in the general population?

TSC2 p.Phe239Cys (c.716T>G) is ultra-rare (popmax 0.0812%, sas) (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.Phe239Cys (c.716T>G)?

AlphaMissense predicts likely pathogenic (score 0.8012) — an in-silico prediction, not a clinical call.

TSC2 p.Phe239Cys

c.716T>G · rs778544723 · VCV207705

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0812%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.8012	likely pathogenic
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	24.6	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 0.0812% South Asian · 74/91,086 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0608%

Overall 0.00459% 74/1,612,618 alleles · ultra-rare exomes 69/1,460,288 · genomes 5/152,330 · joint denominator

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.Phe239Cys
Coding: c.716T>G
MANE Select: NM_000548
dbSNP: rs778544723
Type: single nucleotide variant
Location: chr16:2056711 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 239: an α-helix; the 'required for interaction with tsc1' region

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: tuberous sclerosis 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.Phe239Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Phe239= Conflicting classifications of pathogenicity ★ same residue
TSC2 p.Phe239fs Pathogenic ★ same residue
TSC2 p.Phe239Ser 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

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-phe239cys (accessed [today's date]).

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