Is TK2 p.Val232Leu (c.694G>C) pathogenic?

TK2 p.Val232Leu (c.694G>C) is classified Uncertain significance in TK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.4582); Ultra-rare (popmax 0.04%, afr); Associated with Inborn genetic diseases.

What condition is associated with TK2 p.Val232Leu (c.694G>C)?

TK2 p.Val232Leu (c.694G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TK2 p.Val232Leu (c.694G>C) in the general population?

TK2 p.Val232Leu (c.694G>C) is ultra-rare (popmax 0.04%, afr) (gnomAD).

What do computational predictors say about TK2 p.Val232Leu (c.694G>C)?

AlphaMissense predicts ambiguous (score 0.4582) — an in-silico prediction, not a clinical call.

TK2 p.Val232Leu

c.694G>C · rs576020835 · VCV1372242

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4582 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4582	ambiguous
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -11.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.5, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.04% African / African-American · 30/75,054 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00266% 43/1,614,022 alleles · ultra-rare exomes 25/1,461,712 · genomes 18/152,310 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,502
Middle Eastern	0.0167%	5,972
Admixed American	0.0133%	7,502
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	8.47e-05%	1,180,004

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.Val232Leu
Coding: c.694G>C
MANE Select: NM_004614
dbSNP: rs576020835
Type: single nucleotide variant
Location: chr16:66513736 (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.Val232Ile Uncertain significance ★★ ⚠ 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
TK2 p.Glu246Val 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-val232leu (accessed [today's date]).

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