Is TLK2 p.Arg698Ter (c.2092C>T) pathogenic?

TLK2 p.Arg698Ter (c.2092C>T) is classified Conflicting classifications of pathogenicity in TLK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2020-10-23). Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 57.

What condition is associated with TLK2 p.Arg698Ter (c.2092C>T)?

TLK2 p.Arg698Ter (c.2092C>T) is associated with intellectual disability, autosomal dominant 57 (ClinVar).

How common is TLK2 p.Arg698Ter (c.2092C>T) in the general population?

TLK2 p.Arg698Ter (c.2092C>T) is absent from gnomAD v4.1 (gnomAD).

TLK2 p.Arg698Ter

c.2092C>T · rs1555669421 · VCV489247

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

intellectual disability, autosomal dominant 57

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (22 of 22) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.22	acceptor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4	GERP 2.1, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Arg698Ter
Coding: c.2092C>T
MANE Select: NM_006852
dbSNP: rs1555669421
Type: single nucleotide variant
Location: chr17:62612404 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 698: the protein kinase domain; a UniProt-annotated variant site (in mrd57); a UniProt-annotated variant site (in mrd57; uncertain significance); a turn

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

Disease context

intellectual disability, autosomal dominant 57 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TLK2 p.Arg698Gln Uncertain significance ★ ⚠ same residue
TLK2 c.1121+1G>A Pathogenic/Likely pathogenic ★★ same condition
TLK2 c.1550+1G>A Pathogenic/Likely pathogenic ★★ same condition
TLK2 p.Arg11Ter Likely pathogenic ★★ same condition
TLK2 p.Arg122Ter Pathogenic/Likely pathogenic ★★ same condition
TLK2 p.Arg123Ter Pathogenic ★★ same condition
TLK2 p.Arg262Ter Pathogenic ★★ same condition
TLK2 p.Arg546Trp Pathogenic/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-arg698ter (accessed [today's date]).

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