TBCK p.Pro522=
c.1566A>G · rs145621380 · VCV709735
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.336%, afr)
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 0.78 | GERP -3, phastCons 1 |
| Overall | ||
| CADD | 10.26 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.336%
African / African-American · 252/74,948 alleles
Filtering AF
0.302%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.289%
Overall
0.0176%
283/1,612,232 alleles · rare
exomes 141/1,460,074 · genomes 142/152,158 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.336% | 297 |
| Remaining individualsnot grpmax-eligible | 0.0304% | 3,285 |
| Middle Eastern | 0.0165% | 6,048 |
| Admixed American | 0.0117% | 8,555 |
| South Asian | 0.0011% | 91,032 |
| European (non-Finnish) | 0.000255% | 392,900 |
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.Pro522=
- Coding
- c.1566A>G
- MANE Select
- NM_001163435
- dbSNP
- rs145621380
- Type
- single nucleotide variant
- Location
- chr4:106233011 (GRCh38)
- Gene constraint
- LOEUF 1.062 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 87.42
- Residue 522
- the rab-gap tbc domain
Similar variants
- 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
- TBCK c.266+2T>G 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-pro522 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown