Is TK2 p.Ala73Thr (c.217G>A) pathogenic?

TK2 p.Ala73Thr (c.217G>A) is classified Uncertain significance in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely benign (0.0609); Very rare (popmax 0.005%, amr).

How common is TK2 p.Ala73Thr (c.217G>A) in the general population?

TK2 p.Ala73Thr (c.217G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about TK2 p.Ala73Thr (c.217G>A)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

TK2 p.Ala73Thr

c.217G>A · rs997780363 · VCV1374925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -5.43	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 0.77	GERP -0.24, phastCons 0.43
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	1.139	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 0.005% Admixed American · 3/60,020 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000867% 14/1,614,126 alleles · very rare exomes 14/1,461,844 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,007
East Asian	0.00223%	44,878
Finnishnot grpmax-eligible	0.00156%	64,028
South Asian	0.0011%	91,086
European (non-Finnish)	0.000678%	147,501

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.Ala73Thr
Coding: c.217G>A
MANE Select: NM_004614
dbSNP: rs997780363
Type: single nucleotide variant
Location: chr16:66541893 (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

Similar variants

TK2 p.Ala73Ser Uncertain significance ★ ⚠ same residue
TK2 p.Ala73Val Uncertain significance ★ ⚠ same residue
TK2 p.Ala73= Likely benign ★ same residue
TK2 c.156+2T>C Pathogenic/Likely pathogenic ★★ same type
TK2 c.157-2A>G Pathogenic/Likely pathogenic ★★ same type
TK2 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same type
TK2 p.Ala139Val Pathogenic/Likely pathogenic ★★ same type
TK2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ same type

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-ala73thr (accessed [today's date]).

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