Is TLK2 p.Leu342Ser (c.1025T>C) pathogenic?

TLK2 p.Leu342Ser (c.1025T>C) is classified Likely pathogenic in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-05). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with syndromic microphthalmia.

What condition is associated with TLK2 p.Leu342Ser (c.1025T>C)?

TLK2 p.Leu342Ser (c.1025T>C) is associated with syndromic microphthalmia (ClinVar).

How common is TLK2 p.Leu342Ser (c.1025T>C) in the general population?

TLK2 p.Leu342Ser (c.1025T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Leu342Ser (c.1025T>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

TLK2 p.Leu342Ser

c.1025T>C · VCV4796484

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

syndromic microphthalmia

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic ✓ concordant with ClinVar · top 7% in TLK2
REVEL	0.613	indeterminate
SaProt	LLR -14.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 42 kb · p 3.3e-29 · 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.

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.Leu342Ser
Coding: c.1025T>C
MANE Select: NM_006852
Type: single nucleotide variant
Location: chr17:62573271 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 342: a UniProt-annotated variant site (in mrd57); the 'disordered' region

Full TLK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

syndromic microphthalmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TLK2 c.1121+1G>A Pathogenic/Likely pathogenic ★★ same type
TLK2 c.1550+1G>A Pathogenic/Likely pathogenic ★★ same type
TLK2 p.Arg11Ter Likely pathogenic ★★ same type
TLK2 p.Arg122Ter Pathogenic/Likely pathogenic ★★ same type
TLK2 p.Arg123Ter Pathogenic ★★ same type
TLK2 p.Arg262Ter Pathogenic ★★ same type
TLK2 p.Arg546Trp Pathogenic/Likely pathogenic ★★ same type
TLK2 p.Arg61Ter Pathogenic ★★ same type

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-leu342ser (accessed [today's date]).

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