Is TK2 p.Thr111Ala (c.331A>G) pathogenic?

TK2 p.Thr111Ala (c.331A>G) is classified Conflicting classifications of pathogenicity in TK2 (ClinVar, Conflicting submitters, 1 submitter; last evaluated 2024-03-14). AlphaMissense: likely benign (0.294); Absent from gnomAD v4.1; Associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3.

How common is TK2 p.Thr111Ala (c.331A>G) in the general population?

TK2 p.Thr111Ala (c.331A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TK2 p.Thr111Ala (c.331A>G)?

AlphaMissense predicts likely benign (score 0.294) — an in-silico prediction, not a clinical call.

TK2 p.Thr111Ala

Q: What condition is associated with TK2 p.Thr111Ala (c.331A>G)?

TK2 p.Thr111Ala (c.331A>G) is associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, mitochondrial DNA depletion syndrome, myopathic form (ClinVar).

Q: How is Autosomal recessive progressive external ophthalmoplegia inherited?

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

c.331A>G · VCV3897062

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.294 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Computational evidence

Protein change
AlphaMissense	0.294	likely benign
REVEL	0.648	pathogenic-leaning
SaProt	LLR -11.08	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	25.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TK2
Protein: p.Thr111Ala
Coding: c.331A>G
MANE Select: NM_004614
Type: single nucleotide variant
Location: chr16:66531424 (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

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome, myopathic form

For Autosomal recessive progressive external ophthalmoplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

TK2 p.Thr111Ile 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-thr111ala (accessed [today's date]).

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