TBC1D14

Chr 4

TBC1 domain family member 14

NCBI Gene: 57533 ENSG00000132405 UniProt: Q9P2M4

The TBC1D14 protein regulates autophagosome formation during cellular starvation and controls trafficking of ATG9 from recycling endosomes to the Golgi apparatus to maintain the autophagy initiation machinery. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in infancy. The gene is highly constrained against loss-of-function variants (LOEUF 0.457), indicating intolerance to protein-disrupting mutations.

ResearchSummary from RefSeq, UniProt

Enables protein kinase binding activity. Involved in negative regulation of autophagy; recycling endosome to Golgi transport; and regulation of autophagosome assembly. Located in Golgi apparatus; autophagosome; and recycling endosome. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.039

Z-score 4.12

OE 0.27 (0.17–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.17Z-score

OE missense 0.84 (0.77–0.92)

346 obs / 412.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.17–0.46)

0≤0.351.4

Missense OE?0.84 (0.77–0.92)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 10 / 37.1Missense obs/exp: 346 / 412.7Syn Z: -1.11

Background carrier burden — how many people carry a rare variant somewhere in TBC1D14?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 68

887 rare PASS variants

Rare truncating (LoF)

1 in 2,200

87 rare PASS variants

Rare synonymous (reference)

1 in 84

443 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBC1D14. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 97	1 in 2,400
South Asian	~43k	1 in 53	1 in 2,900
Remaining (unassigned)	~30k	1 in 60	1 in 1,300
European (Finnish)	~27k	1 in 270	1 in 4,800
Admixed American	~22k	1 in 66	1 in 2,400
African / African American	~21k	1 in 52	1 in 1,200
East Asian	~20k	1 in 58	1 in 1,700
Ashkenazi Jewish	~13k	1 in 310	none seen
Middle Eastern	~2,884	1 in 100	≈ 1 in 800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 13 coding exons well covered in gnomAD exomes and genomes.? see exons ↓