Is TLK2 p.Lys396Arg (c.1187A>G) pathogenic?

TLK2 p.Lys396Arg (c.1187A>G) is classified Uncertain significance in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.2804); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with TLK2 p.Lys396Arg (c.1187A>G)?

TLK2 p.Lys396Arg (c.1187A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TLK2 p.Lys396Arg (c.1187A>G) in the general population?

TLK2 p.Lys396Arg (c.1187A>G) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about TLK2 p.Lys396Arg (c.1187A>G)?

AlphaMissense predicts likely benign (score 0.2804) — an in-silico prediction, not a clinical call.

TLK2 p.Lys396Arg

c.1187A>G · VCV3969247

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2804	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 42 kb · p 3.3e-29 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K418R vs ClinVar K396R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,794 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.000435% 7/1,608,406 alleles · ultra-rare exomes 5/1,456,222 · genomes 2/152,184 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,466
African / African-American	0.00134%	74,768

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.Lys396Arg
Coding: c.1187A>G
MANE Select: NM_006852
Type: single nucleotide variant
Location: chr17:62576774 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 418 UniProt numbering: a UniProt-annotated variant site (in mrd57)

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-lys396arg (accessed [today's date]).

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