Is TBCK p.Val69Phe (c.205G>T) pathogenic?

TBCK p.Val69Phe (c.205G>T) is classified Uncertain significance in TBCK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-15). AlphaMissense: likely pathogenic (0.6421); Very rare (popmax 0.000254%, nfe).

How common is TBCK p.Val69Phe (c.205G>T) in the general population?

TBCK p.Val69Phe (c.205G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TBCK p.Val69Phe (c.205G>T)?

AlphaMissense predicts likely pathogenic (score 0.6421) — an in-silico prediction, not a clinical call.

TBCK p.Val69Phe

c.205G>T · rs768434280 · VCV2129555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6421	likely pathogenic
REVEL	0.373	indeterminate
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 262 kb · p 0.62 · regional, not allelic
Overall
CADD	25.4	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 0.000254% European (non-Finnish) · 3/1,179,318 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,206 alleles · very rare exomes 3/1,459,910 · genomes 0/152,296 · joint denominator

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: TBCK
Protein: p.Val69Phe
Coding: c.205G>T
MANE Select: NM_001163435
dbSNP: rs768434280
Type: single nucleotide variant
Location: chr4:106295155 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.42
Residue 69: the protein kinase domain

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

Similar variants

TBCK p.Val69= Likely benign ★ same residue
TBCK c.1170+1G>A Pathogenic/Likely pathogenic ★★ same type
TBCK c.1351-1G>A Likely pathogenic ★★ same type
TBCK c.1775-1G>C Likely pathogenic ★★ same type
TBCK c.1860+1G>A Pathogenic ★★ same type
TBCK c.1897+1G>A Pathogenic ★★ same type
TBCK c.193+1G>T Pathogenic ★★ same type
TBCK c.2060-2A>G Pathogenic/Likely 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/tbck-p-val69phe (accessed [today's date]).

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