Is TK2 p.Arg252Trp (c.754C>T) pathogenic?

TK2 p.Arg252Trp (c.754C>T) is classified Uncertain significance in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-04-23). AlphaMissense: likely benign (0.1885); Very rare (popmax 0.00223%, eas).

How common is TK2 p.Arg252Trp (c.754C>T) in the general population?

TK2 p.Arg252Trp (c.754C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TK2 p.Arg252Trp (c.754C>T)?

AlphaMissense predicts likely benign (score 0.1885) — an in-silico prediction, not a clinical call.

TK2 p.Arg252Trp

c.754C>T · rs373264612 · VCV215264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1885	likely benign
REVEL	0.725	pathogenic-leaning
SaProt	LLR -12.31	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	29.4	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 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,614,158 alleles · very rare exomes 8/1,461,886 · genomes 0/152,272 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.000508%	196,673

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.Arg252Trp
Coding: c.754C>T
MANE Select: NM_004614
dbSNP: rs373264612
Type: single nucleotide variant
Location: chr16:66512012 (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 p.Arg252Gln Uncertain significance ★★ ⚠ same residue
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

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-arg252trp (accessed [today's date]).

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