Is TK2 p.Trp167Ter (c.500G>A) pathogenic?

TK2 p.Trp167Ter (c.500G>A) is classified Pathogenic in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). Very rare (popmax 8.47e-05%, nfe).

How common is TK2 p.Trp167Ter (c.500G>A) in the general population?

TK2 p.Trp167Ter (c.500G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

TK2 p.Trp167Ter

c.500G>A · rs2507091300 · VCV2810054

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 10
Splicing
SpliceAI	Δ0.30	acceptor loss, 50 bp away · masked 0 · deltas
Pangolin	Δ0.25	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 0.78, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.2e-05% 1/1,614,188 alleles · very rare exomes 1/1,461,882 · genomes 0/152,306 · joint denominator

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: TK2
Protein: p.Trp167Ter
Coding: c.500G>A
MANE Select: NM_004614
dbSNP: rs2507091300
Type: single nucleotide variant
Location: chr16:66517827 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01

Full TK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TK2 c.156+2T>C Pathogenic/Likely pathogenic ★★ same type
TK2 c.157-2A>G Pathogenic/Likely pathogenic ★★ same type
TK2 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same type
TK2 p.Ala139Val Pathogenic/Likely pathogenic ★★ same type
TK2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ same type
TK2 p.Arg130Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
TK2 p.Arg130Trp Pathogenic/Likely pathogenic ★★ same type
TK2 p.Arg183Gly Pathogenic/Likely pathogenic ★★ same type

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/tk2-p-trp167ter (accessed [today's date]).

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