Is TSC2 p.Ala84Val (c.251C>T) pathogenic?

TSC2 p.Ala84Val (c.251C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1043); Rare (popmax 0.203%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ala84Val (c.251C>T)?

TSC2 p.Ala84Val (c.251C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, lymphangioleiomyomatosis (ClinVar).

How common is TSC2 p.Ala84Val (c.251C>T) in the general population?

TSC2 p.Ala84Val (c.251C>T) is rare (popmax 0.203%, mid) (gnomAD).

What do computational predictors say about TSC2 p.Ala84Val (c.251C>T)?

AlphaMissense predicts likely benign (score 0.1043) — an in-silico prediction, not a clinical call.

TSC2 p.Ala84Val

c.251C>T · rs35660529 · VCV49212

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.1043 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.203%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1043	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	21.4	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 0.203% Middle Eastern · 11/5,408 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0881%

Overall 0.0325% 517/1,588,838 alleles · rare exomes 484/1,436,482 · genomes 33/152,356 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.203%	492
Ashkenazi Jewishnot grpmax-eligible	0.0997%	1,003
South Asian	0.0805%	1,242
Remaining individualsnot grpmax-eligible	0.0456%	2,195
European (non-Finnish)	0.0313%	3,193
Admixed American	0.023%	4,355

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.Ala84Val
Coding: c.251C>T
MANE Select: NM_000548
dbSNP: rs35660529
Type: single nucleotide variant
Location: chr16:2053367 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 84: 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis lymphangioleiomyomatosis tuberous sclerosis 2

Similar variants

TSC2 p.Ala84Glu Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala84Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala84= 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
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-ala84val (accessed [today's date]).

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