Is TSC2 p.Val1649= (c.4947C>G) pathogenic?

TSC2 p.Val1649= (c.4947C>G) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-13). Very rare (popmax 0.00332%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Val1649= (c.4947C>G)?

TSC2 p.Val1649= (c.4947C>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Val1649= (c.4947C>G) in the general population?

TSC2 p.Val1649= (c.4947C>G) is very rare (popmax 0.00332%, sas) (gnomAD).

TSC2 p.Val1649=

c.4947C>G · rs778989782 · VCV238070

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00332%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.095	GERP 0.75, phastCons 0.91
Overall
CADD	1.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00332% South Asian · 3/90,408 alleles

Filtering AF 0.000881% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000249% 4/1,607,818 alleles · very rare exomes 3/1,455,588 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00332%	30,136
European (non-Finnish)	8.49e-05%	1,178,030

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.Val1649=
Coding: c.4947C>G
MANE Select: NM_000548
dbSNP: rs778989782
Type: single nucleotide variant
Location: chr16:2086829 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1649: the rap-gap domain; a β-strand

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.Val1649Ile 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
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
TSC2 c.138+5G>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-val1649 (accessed [today's date]).

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