Is TLK2 p.Arg421Ser (c.1263G>C) pathogenic?

TLK2 p.Arg421Ser (c.1263G>C) is classified Uncertain significance in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-24). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is TLK2 p.Arg421Ser (c.1263G>C) in the general population?

TLK2 p.Arg421Ser (c.1263G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Arg421Ser (c.1263G>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

TLK2 p.Arg421Ser

c.1263G>C · rs2545779002 · VCV2058006

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 7% in TLK2
REVEL	0.443	indeterminate
SaProt	LLR -16.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Pangolin	Δ0.24	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 0.18, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 34 kb · p 3.2e-51 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R443S vs ClinVar R421S) — verify the residue.

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.Arg421Ser
Coding: c.1263G>C
MANE Select: NM_006852
dbSNP: rs2545779002
Type: single nucleotide variant
Location: chr17:62578551 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 443 UniProt numbering: a UniProt-annotated variant site (in mrd57)

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

Similar variants

TLK2 p.Arg421Lys Uncertain significance ★ ⚠ same residue
TLK2 p.Arg421Met Uncertain significance ★ ⚠ same residue
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

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-arg421ser (accessed [today's date]).

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