Is TLK2 p.Arg339Trp (c.1015C>T) pathogenic?

TLK2 p.Arg339Trp (c.1015C>T) is classified Conflicting classifications of pathogenicity in TLK2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-31). AlphaMissense: likely pathogenic (0.9952); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 57.

What condition is associated with TLK2 p.Arg339Trp (c.1015C>T)?

TLK2 p.Arg339Trp (c.1015C>T) is associated with intellectual disability, autosomal dominant 57 (ClinVar).

How common is TLK2 p.Arg339Trp (c.1015C>T) in the general population?

TLK2 p.Arg339Trp (c.1015C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Arg339Trp (c.1015C>T)?

AlphaMissense predicts likely pathogenic (score 0.9952) — an in-silico prediction, not a clinical call.

TLK2 p.Arg339Trp

c.1015C>T · rs1567948262 · VCV617926

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9952 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, autosomal dominant 57

Computational evidence

Protein change
AlphaMissense	0.9952	likely pathogenic
REVEL	0.476	indeterminate
SaProt	LLR -12.87	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 2.2	GERP 0.16, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 42 kb · p 3.3e-29 · regional, not allelic
Overall
CADD	26.9	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

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.Arg339Trp
Coding: c.1015C>T
MANE Select: NM_006852
dbSNP: rs1567948262
Type: single nucleotide variant
Location: chr17:62573261 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 339: a UniProt-annotated variant site (in mrd57); a UniProt-annotated variant site (in mrd57; uncertain significance)

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.Arg339Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TLK2 p.Arg339Pro 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

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-arg339trp (accessed [today's date]).

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