Is TLK2 p.Ile495Val (c.1483A>G) pathogenic?

TLK2 p.Ile495Val (c.1483A>G) is classified Uncertain significance in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-29). AlphaMissense: likely pathogenic (0.9533); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TLK2 p.Ile495Val (c.1483A>G)?

TLK2 p.Ile495Val (c.1483A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TLK2 p.Ile495Val (c.1483A>G) in the general population?

TLK2 p.Ile495Val (c.1483A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Ile495Val (c.1483A>G)?

AlphaMissense predicts likely pathogenic (score 0.9533) — an in-silico prediction, not a clinical call.

TLK2 p.Ile495Val

c.1483A>G · VCV3969248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9533 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9533	likely pathogenic
REVEL	0.38	indeterminate
SaProt	LLR -10.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 34 kb · p 3.2e-51 · regional, not allelic
Overall
CADD	27.9	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 I517V vs ClinVar I495V) — 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.Ile495Val
Coding: c.1483A>G
MANE Select: NM_006852
Type: single nucleotide variant
Location: chr17:62596607 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 517 UniProt numbering: the protein kinase domain; a UniProt-annotated variant site (in mrd57); a UniProt-annotated variant site (in mrd57; uncertain significance); an α-helix

Full TLK2 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

TLK2 p.Arg546Trp Pathogenic/Likely pathogenic ★★ same condition
TLK2 p.Arg724Gln Uncertain significance ★★ ⚠ same condition
TLK2 p.Thr98Ala Uncertain significance ★★ ⚠ same condition
TLK2 p.Tyr129Cys Uncertain significance ★★ ⚠ same condition
TLK2 p.Lys487= Likely benign ★★ same condition
TLK2 c.1189-2A>G Pathogenic ★ same condition
TLK2 p.Trp643Ter Pathogenic ★ same condition
TLK2 c.1971+2T>C 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/tlk2-p-ile495val (accessed [today's date]).

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