Is TLK2 p.Glu397Asp (c.1191G>C) pathogenic?

TLK2 p.Glu397Asp (c.1191G>C) is classified Uncertain significance in TLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-04). AlphaMissense: likely pathogenic (0.8711); Absent from gnomAD v4.1.

How common is TLK2 p.Glu397Asp (c.1191G>C) in the general population?

TLK2 p.Glu397Asp (c.1191G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TLK2 p.Glu397Asp (c.1191G>C)?

AlphaMissense predicts likely pathogenic (score 0.8711) — an in-silico prediction, not a clinical call.

TLK2 p.Glu397Asp

c.1191G>C · VCV3897076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8711 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8711	likely pathogenic
REVEL	0.25	benign-leaning
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.59	GERP -4.2, phastCons 0.99
Regional constraint	o/e 0.33	constrained · MANE · 42 kb · p 3.3e-29 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E419D vs ClinVar E397D) — 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.Glu397Asp
Coding: c.1191G>C
MANE Select: NM_006852
Type: single nucleotide variant
Location: chr17:62578479 (GRCh38)
Gene constraint: LOEUF 0.103 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.15 · 2 PDB
Residue 419 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 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-glu397asp (accessed [today's date]).

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