Is TK2 p.Ile212Val (c.634A>G) pathogenic?

TK2 p.Ile212Val (c.634A>G) is classified Uncertain significance in TK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.1249); Very rare (popmax 0.00892%, eas); Associated with mitochondrial disease.

What condition is associated with TK2 p.Ile212Val (c.634A>G)?

TK2 p.Ile212Val (c.634A>G) is associated with mitochondrial disease (ClinVar).

How common is TK2 p.Ile212Val (c.634A>G) in the general population?

TK2 p.Ile212Val (c.634A>G) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about TK2 p.Ile212Val (c.634A>G)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

TK2 p.Ile212Val

c.634A>G · VCV3778847

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.474	indeterminate
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.73, phastCons 0.92
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	18.79	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 0.00892% East Asian · 4/44,856 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000372% 6/1,613,896 alleles · very rare exomes 5/1,461,786 · genomes 1/152,110 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,214
European (non-Finnish)	0.000169%	589,998

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.Ile212Val
Coding: c.634A>G
MANE Select: NM_004614
Type: single nucleotide variant
Location: chr16:66513796 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 212: a UniProt-annotated variant site (in mtdps2; reduction of activity in muscles)

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

Disease context

mitochondrial disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TK2 p.Ile212Asn Pathogenic ★★ same residue
TK2 c.156+2T>C Pathogenic/Likely pathogenic ★★ same condition
TK2 c.157-2A>G Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Ala139Val Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg130Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
TK2 p.Arg130Trp 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/tk2-p-ile212val (accessed [today's date]).

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