Is TSC2 p.Phe239Ser (c.716T>C) pathogenic?

TSC2 p.Phe239Ser (c.716T>C) is classified Uncertain significance in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-26). AlphaMissense: likely pathogenic (0.9754); Absent from gnomAD v4.1.

How common is TSC2 p.Phe239Ser (c.716T>C) in the general population?

TSC2 p.Phe239Ser (c.716T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Phe239Ser (c.716T>C)?

AlphaMissense predicts likely pathogenic (score 0.9754) — an in-silico prediction, not a clinical call.

TSC2 p.Phe239Ser

c.716T>C · rs778544723 · VCV1306820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9754 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9754	likely pathogenic · top 10% in TSC2
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -8.76	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	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC2
Protein: p.Phe239Ser
Coding: c.716T>C
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

Similar variants

TSC2 p.Phe239Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Phe239Cys Benign/Likely benign ★★ ⚠ same residue
TSC2 p.Phe239= Conflicting classifications of pathogenicity ★ same residue
TSC2 p.Phe239fs Pathogenic ★ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same type
TSC2 c.1258-2A>G Pathogenic ★★ same type
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same type
TSC2 c.1361+1G>T Pathogenic/Likely pathogenic ★★ same type

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-phe239ser (accessed [today's date]).

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