Is TK2 p.Asp42Asn (c.124G>A) pathogenic?

TK2 p.Asp42Asn (c.124G>A) is classified Likely pathogenic in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely benign (0.092); Very rare (popmax 9.42e-05%, nfe); Associated with mitochondrial DNA depletion syndrome, myopathic form.

What condition is associated with TK2 p.Asp42Asn (c.124G>A)?

TK2 p.Asp42Asn (c.124G>A) is associated with mitochondrial DNA depletion syndrome, myopathic form (ClinVar).

How common is TK2 p.Asp42Asn (c.124G>A) in the general population?

TK2 p.Asp42Asn (c.124G>A) is very rare (popmax 9.42e-05%, nfe) (gnomAD).

What do computational predictors say about TK2 p.Asp42Asn (c.124G>A)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

TK2 p.Asp42Asn

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.124G>A · VCV3767180

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.42e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mitochondrial DNA depletion syndrome, myopathic form

Computational evidence

Protein change
AlphaMissense	0.092	likely benign ⚠ discordant with ClinVar
REVEL	0.291	indeterminate
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.79	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.23	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	25.6	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 9.42e-05% European (non-Finnish) · 1/1,062,052 alleles

Overall 7.38e-05% 1/1,354,376 alleles · very rare exomes 1/1,202,098 · genomes 0/152,278 · joint denominator

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.Asp42Asn
Coding: c.124G>A
MANE Select: NM_004614
Type: single nucleotide variant
Location: chr16:66549938 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 42: the 'disordered' region

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

TK2 p.Asp42Ala Uncertain significance ★ ⚠ same residue
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.Arg130Trp Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg183Trp Pathogenic ★★ ⚠ same condition
TK2 p.Arg192Lys Pathogenic ★★ same condition
TK2 p.Asn58Ser 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-asp42asn (accessed [today's date]).

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