Is TBCK p.Pro20= (c.60A>C) pathogenic?

TBCK p.Pro20= (c.60A>C) is classified Conflicting classifications of pathogenicity in TBCK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-19). Ultra-rare (popmax 0.0822%, mid); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 3.

How common is TBCK p.Pro20= (c.60A>C) in the general population?

TBCK p.Pro20= (c.60A>C) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

TBCK p.Pro20=

Q: What condition is associated with TBCK p.Pro20= (c.60A>C)?

TBCK p.Pro20= (c.60A>C) is associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (ClinVar).

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.60A>C · rs775570874 · VCV1592110

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -6.1
Overall
CADD	4.933	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0822% Middle Eastern · 5/6,084 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00335% 54/1,614,094 alleles · ultra-rare exomes 52/1,461,878 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,217
European (non-Finnish)	0.00398%	25,107
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Pro20=
Coding: c.60A>C
MANE Select: NM_001163435
dbSNP: rs775570874
Type: single nucleotide variant
Location: chr4:106308901 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.42
Residue 20: 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.Pro20Ser Uncertain significance ★ ⚠ same residue
TBCK c.1170+1G>A Pathogenic/Likely pathogenic ★★ same condition
TBCK c.1351-1G>A Likely pathogenic ★★ same condition
TBCK c.1775-1G>C Likely pathogenic ★★ same condition
TBCK c.1860+1G>A Pathogenic ★★ same condition
TBCK c.1897+1G>A Pathogenic ★★ same condition
TBCK c.193+1G>T Pathogenic ★★ same condition
TBCK c.2060-2A>G 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-pro20 (accessed [today's date]).

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