TTLL4

protein-coding

tubulin tyrosine ligase like 4, the group of Tubulin tyrosine ligase family

Gene summary

Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization and protein polyglutamylation. Predicted to act upstream of or within regulation of blastocyst development. Predicted to be located in cytosol. Predicted to be active in ciliary basal body. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_014640.5

Inheritance

—

ClinVar variants

U:175B:12

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr2:218,710,835-218,755,416

External References & Databases

Ensembl (ENSG00000135912)

Transcript & Mutation Effects

hg38 • Region Span ~44.6 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 TTLL4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 171

not providedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014640.5. 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	1 clinvar	3 clinvar	7
missense			170 clinvar	7 clinvar	1 clinvar	178
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	175	8	4	187

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014640.5	RefSeq	NP_055455.3	18	MANE Select
ENST00000392102.6	Ensembl	ENSP00000375951.1	18	MANE Select
ENST00000258398.8	Ensembl	ENSP00000258398.4	18	Standard
ENST00000415717.5	Ensembl	ENSP00000411228.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Carboxyterminal post-translational modifications of tubulin

Biological Process

protein polyglutamylation
peptidyl-glutamic acid modification

Molecular Function

ATP binding
tubulin binding
protein-glutamic acid ligase activity
tubulin-glutamic acid ligase activity

Cellular Component

cytosol
microtubule
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392102
Coding exons: 18
Length: 44572
Individuals with no LoFs: 125482
Homozygous LoFs: 3
Heterozygous LoFs: 263
Defined: 125748
p: 0.00106

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.754	612	667	0.918	0.0000381	7846
Missense (PolyPhen)		108	142.62	0.75725		1715
Synonymous	-0.958	280	260	1.08	0.0000150	2386
Loss of Function	3.45	30	58.4	0.513	0.00000345	626

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.0026	0.0025	notable
Ashkenazi Jewish	0.0012	0.0012	notable
East Asian	0.00033	0.00033	rare
Finnish	0.0010	0.0010	notable
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.00020	0.00016	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Glutamylase which preferentially modifies beta-tubulin and non-tubulin proteins, such as NAP1L1, NAP1L4 and CGAS. Involved in the side-chain initiation step of the polyglutamylation reaction rather than in the elongation step. Involved in formation of short side-chains. Mediates initiation of polyglutamylation of nucleosome assembly proteins NAP1L1 and NAP1L4. Also acts as a monoglutamylase: generates monoglutamylation of CGAS, leading to impair the nucleotidyltransferase activity of CGAS. {ECO:0000250|UniProtKB:Q80UG8}.;

Recessive Scores

pRec: 0.0937

Intolerance Scores

LoFtool: 0.775
RVIS EVS: 1.68
RVIS percentile EVS: 96.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.108

Gene Damage Prediction

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