Is TK2 p.Ala73Ser (c.217G>T) pathogenic?

TK2 p.Ala73Ser (c.217G>T) is classified Uncertain significance in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-02). AlphaMissense: likely benign (0.0755); Very rare (popmax 0.000186%).

How common is TK2 p.Ala73Ser (c.217G>T) in the general population?

TK2 p.Ala73Ser (c.217G>T) is very rare (popmax 0.000186%) (gnomAD).

What do computational predictors say about TK2 p.Ala73Ser (c.217G>T)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

TK2 p.Ala73Ser

c.217G>T · rs997780363 · VCV1349659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000186%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	4.153	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 0.000186%

Overall 0.000186% 3/1,614,126 alleles · very rare exomes 3/1,461,844 · genomes 0/152,282 · 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.Ala73Ser
Coding: c.217G>T
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.Ala73Thr 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-ala73ser (accessed [today's date]).

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