Is TLK2 p.Ile249Phe (c.745A>T) pathogenic?

TLK2 p.Ile249Phe (c.745A>T) is classified Uncertain significance in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-06). AlphaMissense: likely pathogenic (0.6296); Very rare (popmax 0.000849%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TLK2 p.Ile249Phe (c.745A>T)?

TLK2 p.Ile249Phe (c.745A>T) is associated with Inborn genetic diseases (ClinVar).

How common is TLK2 p.Ile249Phe (c.745A>T) in the general population?

TLK2 p.Ile249Phe (c.745A>T) is very rare (popmax 0.000849%, nfe) (gnomAD).

What do computational predictors say about TLK2 p.Ile249Phe (c.745A>T)?

AlphaMissense predicts likely pathogenic (score 0.6296) — an in-silico prediction, not a clinical call.

TLK2 p.Ile249Phe

c.745A>T · VCV4865698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000849%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6296	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 42 kb · p 3.3e-29 · regional, not allelic
Overall
CADD	24.8	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

Grpmax group 0.000849% European (non-Finnish) · 10/1,178,226 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000621% 10/1,610,382 alleles · very rare exomes 10/1,458,098 · genomes 0/152,284 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TLK2
Protein: p.Ile249Phe
Coding: c.745A>T
MANE Select: NM_006852
Type: single nucleotide variant
Location: chr17:62560040 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 249: a UniProt-annotated variant site (in mrd57); the 'required for interaction with tlk1 and dynll1/lc8' region

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-ile249phe (accessed [today's date]).

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