Is TSC2 p.Trp167Arg (c.499T>C) pathogenic?

TSC2 p.Trp167Arg (c.499T>C) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.9944); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Trp167Arg (c.499T>C)?

TSC2 p.Trp167Arg (c.499T>C) is associated with hereditary neoplastic syndrome, tuberous sclerosis, isolated focal cortical dysplasia type II (ClinVar).

How common is TSC2 p.Trp167Arg (c.499T>C) in the general population?

TSC2 p.Trp167Arg (c.499T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TSC2 p.Trp167Arg (c.499T>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

TSC2 p.Trp167Arg

c.499T>C · rs1555498118 · VCV486635

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic · top 3% in TSC2
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,000 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,000
European (non-Finnish)	0.000339%	295,006

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.Trp167Arg
Coding: c.499T>C
MANE Select: NM_000548
dbSNP: rs1555498118
Type: single nucleotide variant
Location: chr16:2055419 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 167: 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 isolated focal cortical dysplasia type II tuberous sclerosis 2

Similar variants

TSC2 p.Trp167Ter Pathogenic ★★ same residue
TSC2 p.Trp167Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Trp167Gly Uncertain significance ★ ⚠ same residue
TSC2 p.Trp167fs 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-trp167arg (accessed [today's date]).

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