Is TBCK p.Pro178fs (c.531dup) pathogenic?

TBCK p.Pro178fs (c.531dup) is classified Pathogenic/Likely pathogenic in TBCK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-15). Very rare (popmax 0.000255%, nfe); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 3.

What condition is associated with TBCK p.Pro178fs (c.531dup)?

TBCK p.Pro178fs (c.531dup) is associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (ClinVar).

How common is TBCK p.Pro178fs (c.531dup) in the general population?

TBCK p.Pro178fs (c.531dup) is very rare (popmax 0.000255%, nfe) (gnomAD).

TBCK p.Pro178fs

Q: How is Hypotonia-speech impairment-severe cognitive delay syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.531dup · rs1560911619 · VCV1033753

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

hypotonia, infantile, with psychomotor retardation and characteristic facies 3

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 6 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
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 0.000255% European (non-Finnish) · 3/1,178,432 alleles

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

Overall 0.000186% 3/1,611,494 alleles · very rare exomes 2/1,459,538 · genomes 1/151,956 · 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.Pro178fs
Coding: c.531dup
MANE Select: NM_001163435
dbSNP: rs1560911619
Type: Duplication
Location: chr4:106251931 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.42
Residue 178: the protein kinase domain

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

Disease context

hypotonia, infantile, with psychomotor retardation and characteristic facies 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypotonia-speech impairment-severe cognitive delay syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TBCK p.His64fs Pathogenic/Likely pathogenic ★★ same condition
TBCK p.Ile698fs Pathogenic ★★ same condition
TBCK p.Lys252Ter Pathogenic ★★ same condition
TBCK p.Ser789fs Pathogenic ★ same condition
TBCK c.193+2dup Uncertain significance ★ same condition
TBCK p.Leu101_Gln102insProPheGluValLeu Conflicting classifications of pathogenicity ★ same condition
TBCK p.Arg529Ter Likely pathogenic same condition
TBCK c.1170+1G>A Pathogenic/Likely pathogenic ★★ same condition

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-pro178fs (accessed [today's date]).

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