Is TSC2 p.Ala623= (c.1869C>T) pathogenic?

TSC2 p.Ala623= (c.1869C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-02-03). Rare (popmax 0.585%, afr); Associated with lymphangioleiomyomatosis.

What condition is associated with TSC2 p.Ala623= (c.1869C>T)?

TSC2 p.Ala623= (c.1869C>T) is associated with lymphangioleiomyomatosis, tuberous sclerosis, isolated focal cortical dysplasia type II (ClinVar).

How common is TSC2 p.Ala623= (c.1869C>T) in the general population?

TSC2 p.Ala623= (c.1869C>T) is rare (popmax 0.585%, afr) (gnomAD).

TSC2 p.Ala623=

c.1869C>T · rs111244727 · VCV137740

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

gnomAD v4.1

Rare

rare (popmax 0.585%, afr)

Conditions

lymphangioleiomyomatosis

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 -8.7	GERP -4.5
Overall
CADD	2.818	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.585% African / African-American · 439/75,042 alleles

Filtering AF 0.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.522%

Overall 0.033% 532/1,613,564 alleles · rare exomes 270/1,461,272 · genomes 262/152,292 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.585%	171
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Admixed American	0.0516%	1,936
Middle Eastern	0.0165%	6,062
South Asian	0.0022%	45,542
European (non-Finnish)	0.00212%	47,201

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.Ala623=
Coding: c.1869C>T
MANE Select: NM_000548
dbSNP: rs111244727
Type: single nucleotide variant
Location: chr16:2071539 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lymphangioleiomyomatosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis isolated focal cortical dysplasia type II tuberous sclerosis 2 hereditary neoplastic syndrome

For Perivascular epithelioid cell neoplasm (Orphanet):

Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

TSC2 p.Ala623Pro Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala623Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala623Ser Uncertain significance ★ ⚠ same residue
TSC2 p.Ala623Val Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala623fs 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

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-ala623 (accessed [today's date]).

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