TTC3

protein-coding

tetratricopeptide repeat domain 3, the group of Tetratricopeptide repeat domain containing|Ring finger proteins

Gene summary

Enables ubiquitin-protein transferase activity. Involved in protein K48-linked ubiquitination and ubiquitin-dependent protein catabolic process. Located in nucleus. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_001330683.2

Inheritance

—

ClinVar variants

U:304B:37

Top phenotype

Corticobasal syndrome

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr21:37,073,226-37,203,112

External References & Databases

Ensembl (ENSG00000182670)

Transcript & Mutation Effects

hg38 • Region Span ~129.9 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 TTC3 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 285

not providedTotal: 20

Corticobasal syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001330683.2. 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			5 clinvar	5 clinvar	7 clinvar	17
missense			278 clinvar	22 clinvar	3 clinvar	303
nonsense			3 clinvar			3
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			17 clinvar			17
Total	0	0	304	27	10	341

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001330683.2	RefSeq	NP_001317612.1	45	MANE Select
ENST00000418766.6	Ensembl	ENSP00000403943.2	45	MANE Select
NM_001001894.3	RefSeq	NP_001001894.1	45	Standard
NM_001320703.2	RefSeq	NP_001307632.1	47	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquitin-dependent protein catabolic process
protein K48-linked ubiquitination

Molecular Function

ubiquitin-protein transferase activity
protein binding
metal ion binding

Cellular Component

nucleus
nucleolus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399017
Coding exons: 45
Length: 129888
Individuals with no LoFs: 125406
Homozygous LoFs: 2
Heterozygous LoFs: 340
Defined: 125748
p: 0.00136

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.596	978	1.03e+3	0.948	0.0000537	13368
Missense (PolyPhen)		194	235.83	0.82261		3267
Synonymous	-0.131	365	362	1.01	0.0000199	3633
Loss of Function	2.55	78	106	0.733	0.00000546	1430

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0019	0.0019	notable
Latino/Admixed American	0.0012	0.0011	notable
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.0021	0.0021	notable
Finnish	0.00085	0.00083	rare
European (Non-Finnish)	0.0012	0.0011	notable
South Asian	0.0026	0.0025	notable
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that mediates the ubiquitination and subsequent degradation of phosphorylated Akt (AKT1, AKT2 and AKT3) in the nucleus. Acts as a terminal regulator of Akt signaling after activation; its phosphorylation by Akt, which is a prerequisite for ubiquitin ligase activity, suggests the existence of a regulation mechanism required to control Akt levels after activation. Catalyzes the formation of 'Lys-48'- polyubiquitin chains. May play a role in neuronal differentiation inhibition via its interaction with CIT. {ECO:0000269|PubMed:17488780, ECO:0000269|PubMed:20059950}.;

Recessive Scores

pRec: 0.0886

Intolerance Scores

LoFtool: 0.992
RVIS EVS: -0.97
RVIS percentile EVS: 8.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.177

Gene Damage Prediction

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