Is TLK2 p.Ser595Pro (c.1783T>C) pathogenic?

TLK2 p.Ser595Pro (c.1783T>C) is classified Likely pathogenic in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 57.

What condition is associated with TLK2 p.Ser595Pro (c.1783T>C)?

TLK2 p.Ser595Pro (c.1783T>C) is associated with intellectual disability, autosomal dominant 57 (ClinVar).

How common is TLK2 p.Ser595Pro (c.1783T>C) in the general population?

TLK2 p.Ser595Pro (c.1783T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Ser595Pro (c.1783T>C)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

TLK2 p.Ser595Pro

c.1783T>C · rs2546025747 · VCV3065405

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 57

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 7% in TLK2
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -13.01	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 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 34 kb · p 3.2e-51 · regional, not allelic
Overall
CADD	32.0	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 S617P vs ClinVar S595P) — 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.Ser595Pro
Coding: c.1783T>C
MANE Select: NM_006852
dbSNP: rs2546025747
Type: single nucleotide variant
Location: chr17:62602104 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 617 UniProt numbering: the protein kinase domain; a UniProt-annotated variant site (in mrd57); a UniProt-annotated variant site (in mrd57; uncertain significance); a UniProt-annotated variant site (in mrd57; exhibits abnormal perinuclear localization instead of diffuse nuclear localization; impairs kinase activity; reduced phosphorylation of asf1a)

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.Ser595Leu Pathogenic/Likely pathogenic ★★ same residue
TLK2 p.Ser595Trp Uncertain significance ★ ⚠ same residue
TLK2 p.Ser595= Likely benign ★ 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

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-ser595pro (accessed [today's date]).

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