Is TBK1 p.Ser243= (c.729T>G) pathogenic?

TBK1 p.Ser243= (c.729T>G) is classified Likely benign in TBK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-04). Very rare (popmax 0.0067%, eas); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 4.

What condition is associated with TBK1 p.Ser243= (c.729T>G)?

TBK1 p.Ser243= (c.729T>G) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (ClinVar).

How common is TBK1 p.Ser243= (c.729T>G) in the general population?

TBK1 p.Ser243= (c.729T>G) is very rare (popmax 0.0067%, eas) (gnomAD).

TBK1 p.Ser243=

Q: How is Frontotemporal dementia with motor neuron disease inherited?

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

c.729T>G · rs539112073 · VCV2178127

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 4

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 2.2	GERP -1.2, phastCons 1
Overall
CADD	11.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0067% East Asian · 3/44,800 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000248% 4/1,612,680 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0067%	14,933
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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: TBK1
Protein: p.Ser243=
Coding: c.729T>G
MANE Select: NM_013254
dbSNP: rs539112073
Type: single nucleotide variant
Location: chr12:64480039 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 89.90 · 25 PDB
Residue 243: the protein kinase domain

Full TBK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

frontotemporal dementia and/or amyotrophic lateral sclerosis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

TBK1 c.1341-1G>A Likely pathogenic ★★ same condition
TBK1 c.701+1G>A Pathogenic ★★ same condition
TBK1 c.992+1G>A Pathogenic ★★ same condition
TBK1 p.Arg117Ter Pathogenic/Likely pathogenic ★★ same condition
TBK1 p.Arg308Ter Pathogenic ★★ same condition
TBK1 p.Arg357Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
TBK1 p.Arg357Ter Pathogenic ★★ same condition
TBK1 p.Arg440Ter 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/tbk1-p-ser243 (accessed [today's date]).

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