Is TK2 p.Ala229Pro (c.685G>C) pathogenic?

TK2 p.Ala229Pro (c.685G>C) is classified Uncertain significance in TK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1041); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with TK2 p.Ala229Pro (c.685G>C)?

TK2 p.Ala229Pro (c.685G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TK2 p.Ala229Pro (c.685G>C) in the general population?

TK2 p.Ala229Pro (c.685G>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about TK2 p.Ala229Pro (c.685G>C)?

AlphaMissense predicts likely benign (score 0.1041) — an in-silico prediction, not a clinical call.

TK2 p.Ala229Pro

c.685G>C · rs750058780 · VCV1413506

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1041	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -0.88	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 -0.72	GERP -2
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	0.373	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 0.0167% Middle Eastern · 1/5,990 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000991% 16/1,613,936 alleles · ultra-rare exomes 16/1,461,734 · genomes 0/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,990
Admixed American	0.00167%	60,008
African / African-American	0.00133%	75,008
European (non-Finnish)	0.0011%	90,765

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.Ala229Pro
Coding: c.685G>C
MANE Select: NM_004614
dbSNP: rs750058780
Type: single nucleotide variant
Location: chr16:66513745 (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.Ala229Thr Uncertain significance ★★ ⚠ same residue
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
TK2 p.Glu246Val Uncertain significance ★★ ⚠ same condition
TK2 p.Glu56Lys 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-ala229pro (accessed [today's date]).

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