Is TLK2 p.Leu577Val (c.1729C>G) pathogenic?

TLK2 p.Leu577Val (c.1729C>G) is classified Uncertain significance in TLK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-10). AlphaMissense: likely pathogenic (0.9859); Absent from gnomAD v4.1; Associated with TLK2-related disorder.

What condition is associated with TLK2 p.Leu577Val (c.1729C>G)?

TLK2 p.Leu577Val (c.1729C>G) is associated with TLK2-related disorder (ClinVar).

How common is TLK2 p.Leu577Val (c.1729C>G) in the general population?

TLK2 p.Leu577Val (c.1729C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Leu577Val (c.1729C>G)?

AlphaMissense predicts likely pathogenic (score 0.9859) — an in-silico prediction, not a clinical call.

TLK2 p.Leu577Val

c.1729C>G · VCV3349778

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9859 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TLK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9859	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -13.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 34 kb · p 3.2e-51 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L599V vs ClinVar L577V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TLK2
Protein: p.Leu577Val
Coding: c.1729C>G
MANE Select: NM_006852
Type: single nucleotide variant
Location: chr17:62602050 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 599 UniProt numbering: the protein kinase domain; a UniProt-annotated variant site (in mrd57); a UniProt-annotated variant site (in mrd57; uncertain significance); a β-strand

Full TLK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TLK2-related disorder

Similar variants

TLK2 p.Leu577Ile Uncertain significance ★ ⚠ same residue
TLK2 p.Arg703Ter Pathogenic/Likely pathogenic ★★ same condition
TLK2 p.Cys195Ter Likely pathogenic ★★ same condition
TLK2 p.Gln252Ter Likely pathogenic ★★ same condition
TLK2 p.His496Arg Pathogenic/Likely pathogenic ★★ same condition
TLK2 p.Pro658Arg Likely pathogenic ★★ same condition
TLK2 p.His193Leu Uncertain significance ★★ ⚠ same condition
TLK2 p.Cys626Tyr Likely pathogenic ★ 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/tlk2-p-leu577val (accessed [today's date]).

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