Is TSC2 p.Ala1622= (c.4866C>T) pathogenic?

TSC2 p.Ala1622= (c.4866C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ala1622= (c.4866C>T)?

TSC2 p.Ala1622= (c.4866C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ala1622= (c.4866C>T) in the general population?

TSC2 p.Ala1622= (c.4866C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

TSC2 p.Ala1622=

c.4866C>T · rs775723717 · VCV1154546

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -3.8, phastCons 0.99
Overall
CADD	8.811	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000891% 13/1,458,472 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
Remaining individualsnot grpmax-eligible	0.0016%	62,330
European (non-Finnish)	0.000847%	117,995

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.Ala1622=
Coding: c.4866C>T
MANE Select: NM_000548
dbSNP: rs775723717
Type: single nucleotide variant
Location: chr16:2086748 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1622: the rap-gap domain; an α-helix

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.Ala1622Gly Uncertain significance ★ ⚠ same residue
TSC2 p.Ala1622Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala1622Val Uncertain significance ★ ⚠ same residue
TSC2 p.Ala1622fs Likely 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

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-ala1622 (accessed [today's date]).

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