Is TK2 p.Glu207Val (c.620A>T) pathogenic?

TK2 p.Glu207Val (c.620A>T) is classified Uncertain significance in TK2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-19). AlphaMissense: likely benign (0.2513); Ultra-rare (popmax 0.013%, nfe); Associated with mitochondrial DNA depletion syndrome, myopathic form.

What condition is associated with TK2 p.Glu207Val (c.620A>T)?

TK2 p.Glu207Val (c.620A>T) is associated with mitochondrial DNA depletion syndrome, myopathic form (ClinVar).

How common is TK2 p.Glu207Val (c.620A>T) in the general population?

TK2 p.Glu207Val (c.620A>T) is ultra-rare (popmax 0.013%, nfe) (gnomAD).

What do computational predictors say about TK2 p.Glu207Val (c.620A>T)?

AlphaMissense predicts likely benign (score 0.2513) — an in-silico prediction, not a clinical call.

TK2 p.Glu207Val

Q: How is Mitochondrial DNA depletion syndrome, myopathic form inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.620A>T · rs141225776 · VCV887483

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2513 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.013%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome, myopathic form

Computational evidence

Protein change
AlphaMissense	0.2513	likely benign
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	31.0	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 0.013% European (non-Finnish) · 153/1,179,996 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.00991% 160/1,613,836 alleles · ultra-rare exomes 149/1,461,776 · genomes 11/152,060 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.013%	7,712
Remaining individualsnot grpmax-eligible	0.0064%	15,618
Admixed American	0.00333%	29,993
African / African-American	0.00134%	74,870

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.Glu207Val
Coding: c.620A>T
MANE Select: NM_004614
dbSNP: rs141225776
Type: single nucleotide variant
Location: chr16:66513810 (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

mitochondrial DNA depletion syndrome, myopathic form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial DNA depletion syndrome, myopathic form (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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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-glu207val (accessed [today's date]).

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