Is TK2 p.Thr80Ala (c.238A>G) pathogenic?

TK2 p.Thr80Ala (c.238A>G) is classified Uncertain significance in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely benign (0.0733); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TK2 p.Thr80Ala (c.238A>G)?

TK2 p.Thr80Ala (c.238A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TK2 p.Thr80Ala (c.238A>G) in the general population?

TK2 p.Thr80Ala (c.238A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TK2 p.Thr80Ala (c.238A>G)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

TK2 p.Thr80Ala

c.238A>G · VCV3456743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -4.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.58, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	15.43	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 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.2e-05% 1/1,614,122 alleles · very rare exomes 1/1,461,886 · genomes 0/152,236 · 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.Thr80Ala
Coding: c.238A>G
MANE Select: NM_004614
Type: single nucleotide variant
Location: chr16:66537011 (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.Thr80Met Uncertain significance ★★ ⚠ same residue
TK2 p.Thr80= 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.Arg261Gln Uncertain significance ★★ ⚠ same condition
TK2 p.Arg261Leu Uncertain significance ★★ ⚠ same condition
TK2 p.Gln110Arg 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-thr80ala (accessed [today's date]).

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