Is TLK2 p.Pro624= (c.1872A>G) pathogenic?

TLK2 p.Pro624= (c.1872A>G) is classified Benign in TLK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-10). Common (popmax 80.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with intellectual disability, autosomal dominant 57.

What condition is associated with TLK2 p.Pro624= (c.1872A>G)?

TLK2 p.Pro624= (c.1872A>G) is associated with intellectual disability, autosomal dominant 57 (ClinVar).

TLK2 p.Pro624=

Q: How common is TLK2 p.Pro624= (c.1872A>G) in the general population?

TLK2 p.Pro624= (c.1872A>G) is common (popmax 80.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1872A>G · rs8078132 · VCV1342219

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 80.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual disability, autosomal dominant 57

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.27, phastCons 1
Overall
CADD	11.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 80.7% East Asian · 34,926/43,264 alleles

Filtering AF 80% ClinGen BA1/BS1 input FAF95, joint · FAF99 79.7%

Overall 58.5% 890,697/1,521,476 alleles · common exomes 813,731/1,369,614 · genomes 76,966/151,862 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	80.7%	1
Amishnot grpmax-eligible	65.6%	2
South Asian	63.1%	2
Finnishnot grpmax-eligible	62.2%	2
European (non-Finnish)	59.8%	2
Ashkenazi Jewishnot grpmax-eligible	58.6%	2
Middle Eastern	58.5%	2
Remaining individualsnot grpmax-eligible	58.3%	2
Admixed American	51.5%	2
African / African-American	24%	4

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.Pro624=
Coding: c.1872A>G
MANE Select: NM_006852
dbSNP: rs8078132
Type: single nucleotide variant
Location: chr17:62606142 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 624: the protein kinase domain; a UniProt-annotated variant site (in mrd57); a UniProt-annotated variant site (in mrd57; uncertain significance); a turn

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 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
TLK2 p.Arg61Ter 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-pro624 (accessed [today's date]).

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