Is TSC2 p.Ala862Val (c.2585C>T) pathogenic?

TSC2 p.Ala862Val (c.2585C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-19). AlphaMissense: ambiguous (0.4354); Ultra-rare (popmax 0.0134%, eas); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Ala862Val (c.2585C>T)?

TSC2 p.Ala862Val (c.2585C>T) is associated with tuberous sclerosis 2, tuberous sclerosis, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ala862Val (c.2585C>T) in the general population?

TSC2 p.Ala862Val (c.2585C>T) is ultra-rare (popmax 0.0134%, eas) (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.Ala862Val (c.2585C>T)?

AlphaMissense predicts ambiguous (score 0.4354) — an in-silico prediction, not a clinical call.

TSC2 p.Ala862Val

c.2585C>T · rs45517249 · VCV50078

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4354 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.4354	ambiguous
REVEL	0.55	indeterminate
SaProt	LLR -6.30	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	22.9	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 0.0134% East Asian · 6/44,898 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00198% 32/1,612,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,483
Remaining individualsnot grpmax-eligible	0.0032%	31,234
South Asian	0.0022%	45,546
European (non-Finnish)	0.00178%	56,191
Finnishnot grpmax-eligible	0.00159%	62,964

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.Ala862Val
Coding: c.2585C>T
MANE Select: NM_000548
dbSNP: rs45517249
Type: single nucleotide variant
Location: chr16:2075838 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 862: an α-helix; a UniProt-annotated variant site (in)

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 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.Ala862Gly Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala862Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala862Thr Conflicting classifications of pathogenicity ★ same residue
TSC2 p.Ala862= Likely benign ★ same residue
TSC2 p.Ala862Leu Uncertain significance ★ 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-ala862val (accessed [today's date]).

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