Is TSC2 p.Asp1478= (c.4434C>T) pathogenic?

TSC2 p.Asp1478= (c.4434C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0164%, mid); Associated with isolated focal cortical dysplasia type II.

What condition is associated with TSC2 p.Asp1478= (c.4434C>T)?

TSC2 p.Asp1478= (c.4434C>T) is associated with isolated focal cortical dysplasia type II, tuberous sclerosis, lymphangioleiomyomatosis (ClinVar).

How common is TSC2 p.Asp1478= (c.4434C>T) in the general population?

TSC2 p.Asp1478= (c.4434C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

TSC2 p.Asp1478=

c.4434C>T · rs758374702 · VCV413681

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

isolated focal cortical dysplasia type II

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 -6.6	GERP -3.6
Overall
CADD	0.166	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

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

Overall 0.00294% 47/1,599,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.0134%	7,476
African / African-American	0.004%	24,971
Remaining individualsnot grpmax-eligible	0.00321%	31,191
European (non-Finnish)	0.00297%	33,710

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.Asp1478=
Coding: c.4434C>T
MANE Select: NM_000548
dbSNP: rs758374702
Type: single nucleotide variant
Location: chr16:2084656 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1478: the 'disordered' region

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

Disease context

isolated focal cortical dysplasia type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis lymphangioleiomyomatosis tuberous sclerosis 2 hereditary neoplastic syndrome

For Isolated focal cortical dysplasia (Orphanet):

Onset: All ages

Similar variants

TSC2 p.Asp1478Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Asp1478Val Uncertain significance ★★ ⚠ same residue
TSC2 p.Asp1478Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Asp1478Glu Uncertain significance ★ ⚠ same residue
TSC2 p.Asp1478His Conflicting classifications of pathogenicity ★ ⚠ 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-asp1478 (accessed [today's date]).

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