Is TLK2 p.Asp59Glu (c.177C>A) pathogenic?

TLK2 p.Asp59Glu (c.177C>A) is classified Likely benign in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely benign (0.1071); Ultra-rare (popmax 0.0134%, afr); Associated with Inborn genetic diseases.

What condition is associated with TLK2 p.Asp59Glu (c.177C>A)?

TLK2 p.Asp59Glu (c.177C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TLK2 p.Asp59Glu (c.177C>A) in the general population?

TLK2 p.Asp59Glu (c.177C>A) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about TLK2 p.Asp59Glu (c.177C>A)?

AlphaMissense predicts likely benign (score 0.1071) — an in-silico prediction, not a clinical call.

TLK2 p.Asp59Glu

c.177C>A · VCV3807240

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1071	likely benign
REVEL	0.424	indeterminate
SaProt	LLR -5.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 55 kb · p 1.6e-14 · regional, not allelic
Overall
CADD	17.42	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 0.0134% African / African-American · 10/74,820 alleles

Filtering AF 0.00724% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00551%

Overall 0.000682% 11/1,612,982 alleles · ultra-rare exomes 5/1,461,026 · genomes 6/151,956 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,482
Admixed American	0.00167%	59,914

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.Asp59Glu
Coding: c.177C>A
MANE Select: NM_006852
Type: single nucleotide variant
Location: chr17:62522227 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 59: the 'disordered' region; 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-asp59glu (accessed [today's date]).

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