TBC1D32

protein-coding

TBC1 domain family member 32, the group of Armadillo like helical domain containing

Gene summary

This gene encodes a TBC-domain containing protein. Studies of a similar protein in mouse and zebrafish suggest that the encoded protein is involved in sonic hedgehog signaling, and that it interacts with and stabilizes cell cycle-related kinase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Previous symbols:

C6orf171
C6orf170

MANE transcript

NM_152730.6

Inheritance

ClinVar variants

P:21U:213B:57

Top phenotype

ciliopathy

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr6:121,079,494-121,334,745

External References & Databases

Ensembl (ENSG00000146350)

Transcript & Mutation Effects

hg38 • Region Span ~255.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

orofaciodigital syndrome IXLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0009795

Submitter: Labcorp Genetics (formerly Invitae)

ciliopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: G2P

orofaciodigital syndrome IXSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009795

Submitter: PanelApp Australia

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*TBC1D32* (TBC1 Domain Family Member 32) is located on 6q22.31. It encodes TBC1 domain family member 32, a TBC-domain containing ciliary protein which plays a crucial role in ciliary function and development, particularly in the retina and brain. The encoded protein is involved in sonic hedgehog signaling (shh), which stabilizes cell cycle-related kinase Ccrk. Together with CDK20, it controls the structure of the primary cilium by coordinating assembly of the ciliary membrane and axoneme, allowing GLI2 to be properly activated in response to Shh signaling. Ciliopathies describe a heterogeneous group of disorders resulting from abnormal ciliary function or structure. *TBC1D32* was first reported in association with autosomal recessive Oral-Facial-Digital Syndrome Type IX in 2020 (PMID: 32573025), Oral-Facial-Digital Syndrome Type IX is characterized by a severe ciliopathy phenotype with clinical features of midline cleft, microcephaly, and colobomatous microphthalmia/anophthalmia with variable presence of polydactyly, absent pituitary and congenital heart disease. Evidence supporting this gene-disease relationship includes case-level and experimental data. 11 variants (including missense, nonsense, splice site and frameshift) reported in 10 probands from 4 publications have been included in this curation (PMID:24285566, 32573025, 32060556, 36826837). Additional clinical evidence can be found in the literature (PMID:37768732; doi.org/10.5734/JGM.2021.18.1.64). These variants are reported in homozygous and compound heterozygous states with loss of function as the mechanism of disease. This gene-disease relationship is also supported by experimental evidence. Knock-out mouse model (bromi) demonstrates that lack of the *TBC1D32* protein leads to grossly abnormal cilia in which large empty spaces are formed on one side of the axoneme in a pattern that suggests abnormal coordination of axoneme and ciliary membrane growth. *bromi* (Broad-Minded) is an ENU-mutagenesis derived mouse line that is characterized by abnormal brain development, severe microphthalmia and polydactyly (PMID: 20159594, 32060556). In summary, there is definitive evidence supporting the relationship between *TBC1D32* related Ciliopathy. This classification is approved by the ClinGen Syndromic Disorders GCEP on the meeting date April 18, 2025.

orofaciodigital syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0015375

Submitter: Franklin by Genoox

Described in this paper in a homozygous patient, as well as reporting previously other reported case in another family with overlapping phenotypes, and another family with two afffected sisters. https://doi.org/10.1002/ajmg.a.61717

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: Illumina

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBC1D32 variants in ClinVar

12 Conditions Cataloged

Inborn genetic diseasesTotal: 173

not providedTotal: 157

TBC1D32-related disorderTotal: 12

Orofaciodigital syndrome IXTotal: 8

Retinitis pigmentosa 100Total: 6

Alsahan-Harris syndromeTotal: 5

CiliopathyTotal: 3

MicrocephalyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152730.6. 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			3 clinvar	29 clinvar	5 clinvar	37
missense			204 clinvar	18 clinvar	5 clinvar	227
nonsense	4 clinvar	3 clinvar				7
start loss						0
frameshift	6 clinvar	3 clinvar	2 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	4 clinvar			9
Total	11	10	213	47	10	291

Highest pathogenic variant AF is 0.000107234155

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152730.6	RefSeq	NP_689943.4	32	MANE Select
ENST00000398212.7	Ensembl	ENSP00000381270.2	32	MANE Select
NM_001367759.1	RefSeq	NP_001354688.1	33	Standard
NM_001367760.1	RefSeq	NP_001354689.1	33	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tbc1d32	Danio rerio	Structure: renal tubule Quality: curled abnormal

Gene / Model

Organism

Observed Phenotype

tbc1d32

Danio rerio

Structure: renal tubule

Quality: curled

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

lens development in camera-type eye
retinal pigment epithelium development
determination of left/right symmetry
heart development
embryonic digit morphogenesis

Cellular Component

cytoplasm
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398212
Coding exons: 32
Length: 255252
Individuals with no LoFs: 124391
Homozygous LoFs: 0
Heterozygous LoFs: 404
Defined: 124795
p: 0.00162

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0369	622	625	0.996	0.0000297	8244
Missense (PolyPhen)		202	205.28	0.98402		2827
Synonymous	-1.26	237	214	1.11	0.00000991	2252
Loss of Function	2.23	52	72.5	0.718	0.00000352	963

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00052	0.00052	rare
Latino/Admixed American	0.0010	0.00096	notable
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.0015	0.0015	notable
Finnish	0.0090	0.0090	notable
European (Non-Finnish)	0.0010	0.0010	notable
South Asian	0.00057	0.00056	rare
Other	0.0017	0.0017	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for high-level Shh responses in the developing neural tube. Together with CDK20, controls the structure of the primary cilium by coordinating assembly of the ciliary membrane and axoneme, allowing GLI2 to be properly activated in response to Shh signaling (By similarity). {ECO:0000250}.;

Intolerance Scores

RVIS EVS: 1.7
RVIS percentile EVS: 96.43

Essentials

Essential (CRISPR): N
Essential (gene trap): N

Gene Damage Prediction

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