Is TBCK p.Phe445fs (c.1334del) pathogenic?

TBCK p.Phe445fs (c.1334del) is classified Pathogenic in TBCK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). Very rare (popmax 0.00422%, afr).

How common is TBCK p.Phe445fs (c.1334del) in the general population?

TBCK p.Phe445fs (c.1334del) is very rare (popmax 0.00422%, afr) (gnomAD).

TBCK p.Phe445fs

c.1334del · rs1560880946 · VCV2909689

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00422%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.14	GERP -0.76, phastCons 0.11
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00422% African / African-American · 3/71,090 alleles

Filtering AF 0.00112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000611%

Overall 0.000264% 4/1,514,158 alleles · very rare exomes 2/1,362,644 · genomes 2/151,514 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00422%	23,697
European (non-Finnish)	8.85e-05%	1,130,424

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.Phe445fs
Coding: c.1334del
MANE Select: NM_001163435
dbSNP: rs1560880946
Type: Deletion
Location: chr4:106236406 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.42

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

Similar variants

TBCK p.Phe445= Benign/Likely benign ★★ same residue
TBCK c.2060-6793_2235+427del Pathogenic ★★ same type
TBCK p.Arg431fs Pathogenic ★★ same type
TBCK p.Asn457fs Pathogenic ★★ same type
TBCK p.Cys353fs Pathogenic/Likely pathogenic ★★ same type
TBCK p.Leu647fs Pathogenic ★★ same type
TBCK p.Lys718fs Pathogenic/Likely pathogenic ★★ same type
TBCK p.Met268fs 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-phe445fs (accessed [today's date]).

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