Is TK2 p.Arg261Leu (c.782G>T) pathogenic?

TK2 p.Arg261Leu (c.782G>T) is classified Uncertain significance in TK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.1178); Very rare (popmax 0.00229%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TK2 p.Arg261Leu (c.782G>T)?

TK2 p.Arg261Leu (c.782G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TK2 p.Arg261Leu (c.782G>T) in the general population?

TK2 p.Arg261Leu (c.782G>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about TK2 p.Arg261Leu (c.782G>T)?

AlphaMissense predicts likely benign (score 0.1178) — an in-silico prediction, not a clinical call.

TK2 p.Arg261Leu

c.782G>T · rs780483040 · VCV1477135

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1178 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1178	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.048	GERP -0.15, phastCons 0.002
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	9.172	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 0.00229% European (non-Finnish) · 27/1,180,034 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00173% 28/1,614,064 alleles · very rare exomes 27/1,461,868 · genomes 1/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,705
Admixed American	0.00167%	60,004

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.Arg261Leu
Coding: c.782G>T
MANE Select: NM_004614
dbSNP: rs780483040
Type: single nucleotide variant
Location: chr16:66511984 (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.Arg261Gln Uncertain significance ★★ ⚠ same residue
TK2 p.Arg261Trp Uncertain significance ★ ⚠ same residue
TK2 p.Arg261= Likely benign ★ same residue
TK2 p.Ala229Pro Uncertain significance ★★ ⚠ same condition
TK2 p.Arg123His Uncertain significance ★★ ⚠ same condition
TK2 p.Arg252Gln Uncertain significance ★★ ⚠ same condition
TK2 p.Gln110Arg Uncertain significance ★★ ⚠ same condition
TK2 p.Glu246Val 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-arg261leu (accessed [today's date]).

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