Is TSC2 p.Ala2Val (c.5C>T) pathogenic?

TSC2 p.Ala2Val (c.5C>T) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.5497); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ala2Val (c.5C>T)?

TSC2 p.Ala2Val (c.5C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ala2Val (c.5C>T) in the general population?

TSC2 p.Ala2Val (c.5C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.5497) — an in-silico prediction, not a clinical call.

TSC2 p.Ala2Val

c.5C>T · rs2084668501 · VCV852633

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5497 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5497	ambiguous
REVEL	0.494	indeterminate
SaProt	LLR -7.88	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.87, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	26.5	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.Ala2Val
Coding: c.5C>T
MANE Select: NM_000548
dbSNP: rs2084668501
Type: single nucleotide variant
Location: chr16:2048620 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 2: 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.Ala2Pro Uncertain significance ★★ same residue
TSC2 p.Ala2Asp Uncertain significance ★ ⚠ same residue
TSC2 p.Ala2Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala2Thr Uncertain significance ★ ⚠ same residue
TSC2 p.Ala2= 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

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-ala2val (accessed [today's date]).

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