Is TK2 p.Arg252Gln (c.755G>A) pathogenic?

TK2 p.Arg252Gln (c.755G>A) is classified Uncertain significance in TK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.1137); Ultra-rare (popmax 0.0668%, eas); Associated with Inborn genetic diseases.

What condition is associated with TK2 p.Arg252Gln (c.755G>A)?

TK2 p.Arg252Gln (c.755G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TK2 p.Arg252Gln (c.755G>A) in the general population?

TK2 p.Arg252Gln (c.755G>A) is ultra-rare (popmax 0.0668%, eas) (gnomAD).

What do computational predictors say about TK2 p.Arg252Gln (c.755G>A)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

TK2 p.Arg252Gln

c.755G>A · rs772329162 · VCV2551891

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.61	indeterminate
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0668% East Asian · 30/44,890 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00204% 33/1,614,028 alleles · ultra-rare exomes 32/1,461,888 · genomes 1/152,140 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0668%	1,496
Admixed American	0.00167%	59,986
European (non-Finnish)	0.000169%	590,019

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.Arg252Gln
Coding: c.755G>A
MANE Select: NM_004614
dbSNP: rs772329162
Type: single nucleotide variant
Location: chr16:66512011 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TK2 p.Arg252Trp Uncertain significance ★ ⚠ same residue
TK2 p.Ala229Pro Uncertain significance ★★ ⚠ same condition
TK2 p.Arg123His Uncertain significance ★★ ⚠ same condition
TK2 p.Arg261Gln Uncertain significance ★★ ⚠ same condition
TK2 p.Arg261Leu Uncertain significance ★★ ⚠ same condition
TK2 p.Gln110Arg Uncertain significance ★★ ⚠ same condition
TK2 p.Glu246Val Uncertain significance ★★ ⚠ same condition
TK2 p.Glu56Lys Uncertain significance ★★ ⚠ 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/tk2-p-arg252gln (accessed [today's date]).

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