TBC1D5

protein-coding

TBC1 domain family member 5

Gene summary

Enables AP-2 adaptor complex binding activity and retromer complex binding activity. Involved in several processes, including macroautophagy; positive regulation of receptor internalization; and retrograde transport, endosome to Golgi. Located in Atg1/ULK1 kinase complex; autophagosome; and cytoplasmic vesicle membrane. Part of retromer complex. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_001349074.2

Inheritance

—

ClinVar variants

U:105B:6

Top phenotype

TBC1D5-related disorder

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr3:17,157,162-18,444,817

External References & Databases

Ensembl (ENSG00000131374)

Transcript & Mutation Effects

hg38 • Region Span ~1,287.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBC1D5 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 100

TBC1D5-related disorderTotal: 4

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001349074.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous						0
missense			102 clinvar	6 clinvar		108
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	105	6	0	111

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 181 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001349074.2	RefSeq	NP_001336003.1	21	MANE Select
ENST00000696125.1	Ensembl	ENSP00000512418.1	21	MANE Select
NM_001134381.2	RefSeq	NP_001127853.1	21	Standard
NM_001349073.2	RefSeq	NP_001336002.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of receptor internalization
intracellular protein transport
autophagy
macroautophagy
retrograde transport, endosome to Golgi

Molecular Function

GTPase activator activity
protein binding
Rab GTPase binding
AP-2 adaptor complex binding
retromer complex binding

Cellular Component

autophagosome
Golgi apparatus
cytosol
endosome membrane
AP-2 adaptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000446818
Coding exons: 21
Length: 1287656
Individuals with no LoFs: 125641
Homozygous LoFs: 0
Heterozygous LoFs: 107
Defined: 125748
p: 0.000426

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.687	383	423	0.906	0.0000210	5404
Missense (PolyPhen)		118	140.01	0.84278		1823
Synonymous	-0.296	158	153	1.03	0.00000816	1497
Loss of Function	1.74	34	46.9	0.725	0.00000250	549

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00026	0.00023	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00060	0.00057	rare
South Asian	0.00044	0.00042	rare
Other	0.00070	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a GTPase-activating protein (GAP) for Rab family protein(s). May act as a GAP for RAB7A. Can displace RAB7A and retromer CSC subcomplex from the endosomal membrane to the cytosol; at least retromer displacement seems to require its catalytic activity (PubMed:19531583, PubMed:20923837). Required for retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN); the function seems to require its catalytic activity. Involved in regulation of autophagy (PubMed:22354992). May act as a molecular switch between endosomal and autophagosomal transport and is involved in reprogramming vesicle trafficking upon autophagy induction. Involved in the trafficking of ATG9A upon activation of autophagy. May regulate the recruitment of ATG9A-AP2-containing vesicles to autophagic membranes (PubMed:24603492). {ECO:0000269|PubMed:19531583, ECO:0000269|PubMed:20923837, ECO:0000269|PubMed:22354992, ECO:0000269|PubMed:24603492, ECO:0000305|PubMed:19531583, ECO:0000305|PubMed:22354992, ECO:0000305|PubMed:24603492}.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.962
RVIS EVS: 0.09
RVIS percentile EVS: 60.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.943

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium