Is TBCK p.Pro20Ser (c.58C>T) pathogenic?

TBCK p.Pro20Ser (c.58C>T) is classified Uncertain significance in TBCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). AlphaMissense: likely benign (0.2961); Very rare (popmax 0.00167%, amr).

How common is TBCK p.Pro20Ser (c.58C>T) in the general population?

TBCK p.Pro20Ser (c.58C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TBCK p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.2961) — an in-silico prediction, not a clinical call.

TBCK p.Pro20Ser

c.58C>T · rs1193957323 · VCV2005382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2961	likely benign
REVEL	0.393	indeterminate
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 262 kb · p 0.62 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,018 alleles

Overall 6.2e-05% 1/1,614,110 alleles · very rare exomes 1/1,461,866 · genomes 0/152,244 · 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.Pro20Ser
Coding: c.58C>T
MANE Select: NM_001163435
dbSNP: rs1193957323
Type: single nucleotide variant
Location: chr4:106308903 (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

Similar variants

TBCK p.Pro20= Conflicting classifications of pathogenicity ★ 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-pro20ser (accessed [today's date]).

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