GeneBe

TTC12

protein-coding

tetratricopeptide repeat domain 12, the group of Armadillo like helical domain containing|Tetratricopeptide repeat domain containing

Gene summary

Involved in axonemal dynein complex assembly and sperm axoneme assembly. Located in centrosome and cytoplasm. Implicated in acute lymphoblastic leukemia; alcohol dependence; drug dependence (multiple); nicotine dependence; and primary ciliary dyskinesia 45. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_017868.4

Inheritance

AR, AD

ClinVar variants

P:9U:99B:23

Top phenotype

Primary ciliary dyskinesia 45

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr11:113,314,579-113,383,544

External References & Databases

Ensembl (ENSG00000149292)NCBI Gene (54970)OMIM (610732)HGNC:23700GenCCUniProt (Q9H892)AlphaFoldClinVar (TTC12)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~69.0 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliary dyskinesia, primary, 45MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032924

Submitter: Ambry Genetics

ciliary dyskinesia, primary, 45DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032924

Submitter: ClinGen

The tetratricopeptide repeat domain 12 (*TTC12*) gene encodes a cytoplasmic protein of the tetratricopeptide repeat gene family. The gene was first shown to function in dynein assembly in motile cilia and flagella and was first implicated in primary ciliary dyskinesia in 2020 (Thomas et al., PMID: 31978331). Common patient phenotypes included recurrent upper and lower respiratory infections, bronchiectasis, and respiratory ciliary axonemes characterized by absence of inner dynein arms and varying degrees of disorganization detected by transmission electron microscopy, and male infertility due to asthenospermia (PMID: 31978331). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism and autosomal recessive mode of inheritance to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, the asserted cases associated with *TTC12 *variants, were curated for a single disease entity, primary ciliary dyskinesia, 45 (MONDO: 0032924). This curation includes 11 variants (splice site, nonsense, frameshift and missense) reported in four publications (PMID: 31978331, PMID: 36273201, PMID: 37325566, PMID: 38992144). Absence of TTC12 immunofluorescence signal from proband samples was consistent with a loss-of-function mechanism of pathogenicity. Experimental evidence supporting this gene disease relationship includes transmission electron microscopic analysis of sperm cells from patients carrying biallelic *TTC12* variants, revealing total lack of both inner and outer dynein arms and diminished TTC12 and DNAH17 signals in the patient spermatozoa relative to controls (PMID: 31978331, PMID: 37325566). Knockdown of TTC12a+b in Paramecia recapitulated the sperm phenotype and led to loss of both ODAs and IDAs. The swimming velocity and cell death observed in TTC12a-depleted cells were successfully rescued by the expression of an RNAi-resistant version of the gene (PMID: 31978331). In summary, *TTC12* is definitively associated with autosomal recessive primary ciliary dyskinesia 45. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Motile Ciliopathy GCEP on May 8th, 2025 (SOP version 11).

ciliary dyskinesia, primary, 45STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032924

Submitter: Labcorp Genetics (formerly Invitae)

primary ciliary dyskinesiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

ciliary dyskinesia, primary, 45STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032924

Submitter: PanelApp Australia

ciliary dyskinesia, primary, 45STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032924

Submitter: G2P

Clinical Genomic Database (CGD)

Primary ciliary dyskinesia 45AR

Manifestation: Allergy/Immunology/Infectious; Genitourinary; Pulmonary

Intervention: Allergy/Immunology/Infectious; Pulmonary

Rationale: Pulmonary surveillance may be beneficial to assess respiratory function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial

Refs: 31978331Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TTC12 variants in ClinVar

7 Conditions Cataloged
Inborn genetic diseasesTotal: 105
not providedTotal: 15
TTC12-related disorderTotal: 12
not specifiedTotal: 8
Ciliary dyskinesia, primary, 45Total: 7
Abnormal sperm morphologyTotal: 3
Reduced sperm motilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017868.4. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
1
clinvar
 10
missense
2
clinvar
97
clinvar
12
clinvar
 111
nonsense
2
clinvar
 2
start loss
0
frameshift
3
clinvar
2
clinvar
 5
splice donor/acceptor (+/-2bp)
2
clinvar
1
clinvar
 3
Total7299212131

Highest pathogenic variant AF is 0.00010782179

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_017868.4RefSeqNP_060338.321MANE Select
ENST00000529221.6EnsemblENSP00000433757.121MANE Select
NM_001318533.2RefSeqNP_001305462.121Standard
NM_001352037.2RefSeqNP_001338966.120Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

  • centrosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000529221
Coding exons
21
Length
69016
Individuals with no LoFs
124730
Homozygous LoFs
10
Heterozygous LoFs
1008
Defined
125748
p
0.00406
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.09273823771.010.00001974622
Missense (PolyPhen)8895.7490.919071164
Synonymous-0.3981501441.040.000007971326
Loss of Function1.313139.90.7770.00000204495

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000920.00092rare
Latino/Admixed American0.0190.019notable
Ashkenazi Jewish0.000600.00060rare
East Asian0.0110.011notable
Finnish0.000370.00037rare
European (Non-Finnish)0.000700.00069rare
South Asian0.00180.0016notable
Other0.00290.0029notable

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec
0.0969

Intolerance Scores

LoFtool
0.911
RVIS EVS
-0.15
RVIS percentile EVS
42.25

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.599

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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