Is TSC2 p.Leu796Val (c.2386C>G) pathogenic?

TSC2 p.Leu796Val (c.2386C>G) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-10). AlphaMissense: ambiguous (0.4907); Very rare (popmax 8.47e-05%, nfe); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Leu796Val (c.2386C>G)?

TSC2 p.Leu796Val (c.2386C>G) is associated with tuberous sclerosis 2, tuberous sclerosis, lymphangioleiomyomatosis (ClinVar).

How common is TSC2 p.Leu796Val (c.2386C>G) in the general population?

TSC2 p.Leu796Val (c.2386C>G) is very rare (popmax 8.47e-05%, nfe) (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.Leu796Val (c.2386C>G)?

AlphaMissense predicts ambiguous (score 0.4907) — an in-silico prediction, not a clinical call.

TSC2 p.Leu796Val

c.2386C>G · rs1596356291 · VCV650089

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.4907	ambiguous
REVEL	0.745	pathogenic-leaning
SaProt	LLR -10.41	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	25.4	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 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 6.2e-05% 1/1,612,184 alleles · very rare exomes 1/1,459,826 · genomes 0/152,358 · 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.Leu796Val
Coding: c.2386C>G
MANE Select: NM_000548
dbSNP: rs1596356291
Type: single nucleotide variant
Location: chr16:2074230 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 796: an α-helix

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 lymphangioleiomyomatosis isolated focal cortical dysplasia type II 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.Leu796Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Leu796= Likely benign ★ same residue
TSC2 p.Leu796fs Pathogenic ★ 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-leu796val (accessed [today's date]).

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