Is TSC2 p.Val249Phe (c.745G>T) pathogenic?

TSC2 p.Val249Phe (c.745G>T) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.2994); No allele count reported in gnomAD v4.1 (AN 1,611,410); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Val249Phe (c.745G>T)?

TSC2 p.Val249Phe (c.745G>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Val249Phe (c.745G>T) in the general population?

TSC2 p.Val249Phe (c.745G>T) is no allele count reported in gnomAD v4.1 (AN 1,611,410) (gnomAD).

What do computational predictors say about TSC2 p.Val249Phe (c.745G>T)?

AlphaMissense predicts likely benign (score 0.2994) — an in-silico prediction, not a clinical call.

TSC2 p.Val249Phe

c.745G>T · VCV3703510

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2994 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,611,410)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2994	likely benign
REVEL	0.583	indeterminate
SaProt	LLR -6.66	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 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	23.7	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

No allele count reported in gnomAD v4.1 (AN 1,611,410). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TSC2
Protein: p.Val249Phe
Coding: c.745G>T
MANE Select: NM_000548
Type: single nucleotide variant
Location: chr16:2056740 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 249: the 'required for interaction with tsc1' region

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 2

Similar variants

TSC2 p.Val249Ala Uncertain significance ★★ same residue
TSC2 p.Val249Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Val249Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Val249= 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
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-val249phe (accessed [today's date]).

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