Is TLK2 p.Pro658Arg (c.1973C>G) pathogenic?

TLK2 p.Pro658Arg (c.1973C>G) is classified Likely pathogenic in TLK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-01). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with TLK2-related disorder.

What condition is associated with TLK2 p.Pro658Arg (c.1973C>G)?

TLK2 p.Pro658Arg (c.1973C>G) is associated with TLK2-related disorder, intellectual disability, autosomal dominant 57 (ClinVar).

How common is TLK2 p.Pro658Arg (c.1973C>G) in the general population?

TLK2 p.Pro658Arg (c.1973C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Pro658Arg (c.1973C>G)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

TLK2 p.Pro658Arg

c.1973C>G · rs1568018905 · VCV617915

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9996 · 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	0.9996	likely pathogenic ✓ concordant with ClinVar · top 7% in TLK2
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -15.71	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	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P680R vs ClinVar P658R) — 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.Pro658Arg
Coding: c.1973C>G
MANE Select: NM_006852
dbSNP: rs1568018905
Type: single nucleotide variant
Location: chr17:62608042 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 658: the protein kinase domain; 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

TLK2-related disorder

Also linked: intellectual disability, autosomal dominant 57

Similar variants

TLK2 p.Pro658Leu 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-pro658arg (accessed [today's date]).

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