Is TSC2 p.Val78= (c.234G>A) pathogenic?

TSC2 p.Val78= (c.234G>A) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-07). Very rare (popmax 0.00231%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Val78= (c.234G>A)?

TSC2 p.Val78= (c.234G>A) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Val78= (c.234G>A) in the general population?

TSC2 p.Val78= (c.234G>A) is very rare (popmax 0.00231%, sas) (gnomAD).

TSC2 p.Val78=

c.234G>A · rs1347487177 · VCV753532

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00231%, sas)

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 0.24	GERP -0.49, phastCons 0.94
Overall
CADD	7.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00231% South Asian · 2/86,512 alleles

Filtering AF 0.000384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000144%

Overall 0.000379% 6/1,584,536 alleles · very rare exomes 4/1,432,278 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00231%	43,256
East Asian	0.0023%	43,456
European (non-Finnish)	0.000257%	388,827

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.Val78=
Coding: c.234G>A
MANE Select: NM_000548
dbSNP: rs1347487177
Type: single nucleotide variant
Location: chr16:2053350 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 78: 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 2

Similar variants

TSC2 p.Val78Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Val78Glu 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
TSC2 c.1361+1G>T Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1362-1G>A Pathogenic ★★ same condition
TSC2 c.138+2T>C 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-val78 (accessed [today's date]).

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