TBC1D24

Chr 16ADAR

TBC1 domain family member 24

Also known as: DEE16, DFNA65, DFNB86, DOORS, EIEE16, EIM, EPRPDC, FIME

NCBI Gene: 57465 ENSG00000162065 UniProt: Q9ULP9 OMIM: 613577

The protein functions as a GTPase-activating protein that regulates Rab small GTPases involved in membrane trafficking. Mutations cause a spectrum of disorders including developmental and epileptic encephalopathy, familial infantile myoclonic epilepsy, DOORS syndrome, and both autosomal dominant and recessive forms of deafness. The condition follows both autosomal dominant and autosomal recessive inheritance patterns, with pathogenicity resulting from disrupted membrane trafficking regulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 1.126 OMIM phenotypes

Clinical Summary— TBC1D24

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Gene-Disease Validity (ClinGen)

DOORS syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

110 unique Pathogenic / Likely Pathogenic· 533 VUS of 1062 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TBC1D24

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.12LOEUF

pLI 0.000

Z-score 1.14

OE 0.73 (0.49–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.76Z-score

OE missense 0.89 (0.81–0.97)

312 obs / 351.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.49–1.12)

0≤0.351.4

Missense OE?0.89 (0.81–0.97)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 15 / 20.6Missense obs/exp: 312 / 351.9Syn Z: -0.99

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTBC1D24-related DOORS syndromeLOFAR

definitiveTBC1D24-related myoclonic epilepsy, infantile, familialOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4785th %ile

GOF

0.5464th %ile

LOF

0.3941th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

LOFImportantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 30335140 ↗

ClinVar Variant Classifications

1062 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71

Likely Pathogenic39

VUS533

Likely Benign293

Benign39

Conflicting77

Pathogenic

Likely Pathogenic

533

VUS

293

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	51	16	4	0	71
Likely Pathogenic	20	19	0	0	39
VUS	4	408	112	9	533
Likely Benign	0	5	100	188	293
Benign	0	0	36	3	39
Conflicting	—				77
Total	75	448	252	200	1,052

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 50) ClinVar copy-number / structural variants overlap TBC1D24 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →