TTLL5

Summary

TTLL5 (tubulin tyrosine ligase like 5, HGNC:19963) is a protein-coding gene on chromosome 14q24.3, encoding Tubulin polyglutamylase TTLL5 (Q6EMB2). Polyglutamylase which modifies tubulin, generating polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin.

This gene encodes a member of the tubulin tyrosine ligase like protein family. This protein interacts with two glucocorticoid receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. This protein may function as a coregulator of glucocorticoid receptor mediated gene induction and repression. This protein may also function as an alpha tubulin polyglutamylase.

Source: NCBI Gene 23093 — RefSeq curated summary.

At a glance

• Gene–disease (curated): TTLL5-related retinopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,153 total — 81 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 24
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_015072

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19963
Approved symbol	TTLL5
Name	tubulin tyrosine ligase like 5
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	STAMP
Ensembl gene	ENSG00000119685
Ensembl biotype	protein_coding
OMIM	612268
Entrez	23093

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 20 protein_coding, 14 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000286650, ENST00000298832, ENST00000554132, ENST00000554148, ENST00000554185, ENST00000554487, ENST00000554510, ENST00000554878, ENST00000554935, ENST00000554972, ENST00000555018, ENST00000555290, ENST00000555422, ENST00000556173, ENST00000556265, ENST00000556685, ENST00000556893, ENST00000556976, ENST00000556977, ENST00000557219, ENST00000557636, ENST00000608522, ENST00000882579, ENST00000882580, ENST00000882581, ENST00000882582, ENST00000882583, ENST00000939617, ENST00000939618, ENST00000939619, ENST00000939620, ENST00000939621, ENST00000939622, ENST00000969079, ENST00000969080

RefSeq mRNA: 1 — MANE Select: NM_015072 NM_015072

CCDS: CCDS32124

Canonical transcript exons

ENST00000298832 — 32 exons

Exon	Start	End
ENSE00000808411	75776747	75776850
ENSE00000808412	75779575	75779702
ENSE00000808415	75792916	75793100
ENSE00000808419	75863667	75863862
ENSE00000808421	75882685	75882902
ENSE00001256947	75783147	75783530
ENSE00001257007	75954424	75955079
ENSE00001730527	75717861	75717962
ENSE00003472769	75745490	75745581
ENSE00003474552	75766062	75766368
ENSE00003486925	75683550	75683656
ENSE00003509783	75752893	75752955
ENSE00003525637	75902142	75902224
ENSE00003535006	75745095	75745208
ENSE00003542192	75690192	75690322
ENSE00003544885	75775484	75775630
ENSE00003548983	75707623	75707707
ENSE00003551967	75733989	75734050
ENSE00003561207	75735195	75735289
ENSE00003568672	75720596	75720703
ENSE00003575694	75782487	75782573
ENSE00003591632	75820007	75820161
ENSE00003616911	75764615	75764772
ENSE00003621753	75707018	75707087
ENSE00003625930	75663055	75663223
ENSE00003646094	75719735	75719826
ENSE00003652642	75771734	75771854
ENSE00003657787	75699188	75699270
ENSE00003660559	75681545	75681627
ENSE00003670952	75732338	75732419
ENSE00003689326	75669416	75669522
ENSE00003842922	75661246	75661387

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.2091 / max 237.3726, expressed in 1793 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140702	15.2091	1793
140703	1.3708	673
140700	0.4381	244
140701	0.3331	131

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	97.62	gold quality
right testis	UBERON:0004534	97.45	gold quality
testis	UBERON:0000473	96.53	gold quality
sperm	CL:0000019	94.82	gold quality
sural nerve	UBERON:0015488	93.93	gold quality
male germ cell	CL:0000015	93.91	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.06	gold quality
buccal mucosa cell	CL:0002336	91.74	gold quality
bronchial epithelial cell	CL:0002328	91.06	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.88	gold quality
epithelium of bronchus	UBERON:0002031	90.70	gold quality
tendon of biceps brachii	UBERON:0008188	90.51	gold quality
bronchus	UBERON:0002185	90.24	gold quality
corpus callosum	UBERON:0002336	90.08	gold quality
colonic epithelium	UBERON:0000397	90.03	gold quality
right uterine tube	UBERON:0001302	90.03	gold quality
adult organism	UBERON:0007023	89.97	gold quality
spinal cord	UBERON:0002240	89.72	gold quality
cortical plate	UBERON:0005343	89.43	gold quality
ventricular zone	UBERON:0003053	89.17	gold quality
adrenal tissue	UBERON:0018303	89.16	gold quality
ganglionic eminence	UBERON:0004023	89.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.68	gold quality
calcaneal tendon	UBERON:0003701	88.34	gold quality
tendon	UBERON:0000043	88.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.45	gold quality
tongue squamous epithelium	UBERON:0006919	85.76	gold quality
medial globus pallidus	UBERON:0002477	85.24	gold quality
pancreatic ductal cell	CL:0002079	85.21	gold quality
fallopian tube	UBERON:0003889	85.00	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting TTLL5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-100-3P	99.20	67.33	672
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-4646-3P	98.65	66.98	693
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-3944-5P	98.50	67.55	997
HSA-MIR-6810-5P	98.29	66.21	975

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• STAMP is an important new, downstream component of GR action in both gene activation and gene repression. (PMID:17116691)
• This study indicates that a physiological function of STAMP in several settings is to modify cell growth rates in a manner that can be independent of steroid hormones. (PMID:20374646)
• this study has performed exome sequencing in 28 individuals with a similar disease phenotype and subsequently used a casecontrol approach to identify mutations in TTLL5 as a cause of recessive retinal dystrophy. (PMID:24791901)
• 5 homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe) and p.(Glu543Lys)] in TTLL5, in 8 patients from 6 families were identified. 2 male patients carrying truncating TTLL5 variants also displayed a reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. TTLL has multiple viable isoforms, being highly expressed in retina, testis and spermatozoon flagellum. (PMID:28173158)
• in a study of 3 family members from 2 generations, identified in a previously misdiagnosed incomplete congenital stationary night blindness (icCSNB) case a splice-site mutation in intron 3 of TTLL5 (c.182-3_182-1delinsAA); reinvestigation of the clinical data corrected the diagnosis to cone dystrophy (PMID:28356705)
• Binding of CSAP to TTLL5 promotes relocalization of TTLL5 toward microtubules. (PMID:30517872)
• Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy. (PMID:34203883)
• Expanding the phenotype of TTLL5-associated retinal dystrophy: a case series. (PMID:35365235)
• Impaired glutamylation of RPGR[ORF15] underlies the cone-dominated phenotype associated with truncating distal ORF15 variants. (PMID:36445968)
• Novel pathogenic variants in Tubulin Tyrosine Like 5 (TTLL5) associated with cone-dominant retinal dystrophies and an abnormal optical coherence tomography phenotype. (PMID:38264610)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Tubulin polyglutamylase TTLL5 — Q6EMB2 (reviewed: Q6EMB2)

Alternative names: SRC1 and TIF2-associated modulatory protein, Tubulin–tyrosine ligase-like protein 5

All UniProt accessions (5): Q6EMB2, A0A087WUG0, G3V2J9, G3V4R8, Q2TAY9

UniProt curated annotations — full annotation on UniProt →

Function. Polyglutamylase which modifies tubulin, generating polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin. Preferentially mediates ATP-dependent initiation step of the polyglutamylation reaction over the elongation step. Preferentially modifies the alpha-tubulin tail over a beta-tail. Required for CCSAP localization to both polyglutamylated spindle and cilia microtubules. Increases the effects of transcriptional coactivator NCOA2/TIF2 in glucocorticoid receptor-mediated repression and induction and in androgen receptor-mediated induction.

Subunit / interactions. Interacts with the transcriptional coactivators NCOA1/SRC-1 and NCOA2/TIF2.

Subcellular location. Cell projection. Cilium. Cytoplasm. Cytoskeleton. Cilium basal body. Nucleus.

Tissue specificity. Expressed in the retina, found in the rod and cone photoreceptors (at protein level). Widely expressed with highest levels in heart and skeletal muscle and low levels in other tissues.

Disease relevance. Cone-rod dystrophy 19 (CORD19) [MIM:615860] A form of cone-rod dystrophy, an inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The flexible c-MTBD (cationic microtubule binding domain) region mediates binding to microtubules. It is positively charged and becomes ordered when bound to microtubules: it interacts with a negatively charged patch on tubulin. The presence of positive charges in the c-MTBD region is essential for proper binding. Arg-186 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin–tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.

Similarity. Belongs to the tubulin–tyrosine ligase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6EMB2-1	1	yes
Q6EMB2-2	2
Q6EMB2-3	3

RefSeq proteins (1): NP_055887* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004344	TTL/TTLL_fam	Family

Pfam: PF03133

Catalyzed reactions (Rhea), 2 shown:

• L-glutamyl-[protein] + L-glutamate + ATP = gamma-L-glutamyl-L-glutamyl-[protein] + ADP + phosphate + H(+) (RHEA:60144)
• (L-glutamyl)(n)-gamma-L-glutamyl-L-glutamyl-[protein] + L-glutamate + ATP = (L-glutamyl)(n+1)-gamma-L-glutamyl-L-glutamyl-[protein] + ADP + phosphate + H(+) (RHEA:60148)

UniProt features (40 total): binding site 15, sequence variant 7, compositionally biased region 5, splice variant 5, region of interest 4, chain 1, domain 1, site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9PHH	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6EMB2-F1	62.56	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 186 (essential for specifying initiation versus elongation step of the polyglutamylase activity)

Ligand- & substrate-binding residues (15): 180; 186–187; 186; 208–211; 221–223; 247; 268–269; 270; 271; 293; 353; 366 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
467–473	decreased binding to microtubules and polyglutamylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8955332	Carboxyterminal post-translational modifications of tubulin

MSigDB gene sets: 182 (showing top): MORF_MSH3, MORF_BRCA1, MORF_ATRX, GOBP_MALE_GAMETE_GENERATION, GOCC_MICROTUBULE_ORGANIZING_CENTER, chr14q24, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOCC_CENTROSOME, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GGCAGTG_MIR3243P, GOBP_PEPTIDYL_GLUTAMIC_ACID_MODIFICATION, GOBP_MICROTUBULE_BUNDLE_FORMATION

GO Biological Process (3): sperm axoneme assembly (GO:0007288), retina development in camera-type eye (GO:0060041), protein modification process (GO:0036211)

GO Molecular Function (8): ATP binding (GO:0005524), tubulin binding (GO:0015631), metal ion binding (GO:0046872), tubulin-glutamic acid ligase activity (GO:0070740), protein-glutamic acid ligase activity, initiating (GO:0106437), protein-glutamic acid ligase activity, elongating (GO:0106438), nucleotide binding (GO:0000166), ligase activity (GO:0016874)

GO Cellular Component (10): nucleus (GO:0005634), centrosome (GO:0005813), cytosol (GO:0005829), microtubule (GO:0005874), plasma membrane (GO:0005886), ciliary basal body (GO:0036064), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein-glutamic acid ligase activity	3
cellular anatomical structure	3
microtubule organizing center	2
developmental process involved in reproduction	1
axoneme assembly	1
sperm flagellum assembly	1
camera-type eye development	1
anatomical structure development	1
protein metabolic process	1
macromolecule modification	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cytoskeletal protein binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
centriole	1
cytoplasm	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
membrane	1
cell periphery	1
cilium	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

762 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTLL5	TSC22D3	Q99576	713
TTLL5	RPGR	Q92834	620
TTLL5	CFAP418	Q96NL8	586
TTLL5	CCDC138	Q96M89	572
TTLL5	TTLL4	Q14679	570
TTLL5	AGBL5	Q8NDL9	568
TTLL5	AGTPBP1	Q9UPW5	560
TTLL5	ATAT1	Q5SQI0	544
TTLL5	AGBL4	Q5VU57	542
TTLL5	DRC9	Q9H095	541
TTLL5	POC1B	Q8TC44	540
TTLL5	CCDC61	Q9Y6R9	539
TTLL5	NCOA2	Q15596	536
TTLL5	TTLL9	Q3SXZ7	532
TTLL5	TTLL11	Q8NHH1	532

IntAct

44 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
CACNG5	ZNF316	psi-mi:“MI:0914”(association)	0.530
ODAD4	GNPAT	psi-mi:“MI:0914”(association)	0.530
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
TTLL5	DNAJA2	psi-mi:“MI:0914”(association)	0.530
TSGA10IP	TTLL5	psi-mi:“MI:0914”(association)	0.530
ZNRD2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
TTLL5	FXR1	psi-mi:“MI:0915”(physical association)	0.370
Cep135		psi-mi:“MI:0914”(association)	0.350
Cep120	TBC1D31	psi-mi:“MI:0914”(association)	0.350
CEP43	CCHCR1	psi-mi:“MI:0914”(association)	0.350
PTTG1	PMS1	psi-mi:“MI:0914”(association)	0.350
Cep131	WBP2	psi-mi:“MI:0914”(association)	0.350
OFD1	CCDC14	psi-mi:“MI:0914”(association)	0.350
CEP135	TBC1D31	psi-mi:“MI:0914”(association)	0.350
Cep43	TBC1D31	psi-mi:“MI:0914”(association)	0.350
Ankrd26	TBC1D31	psi-mi:“MI:0914”(association)	0.350
Lrrcc1	CCDC14	psi-mi:“MI:0914”(association)	0.350
Cep72	TBC1D31	psi-mi:“MI:0914”(association)	0.350
Setd5	NCOR2	psi-mi:“MI:0914”(association)	0.350
GAR1	TAF1	psi-mi:“MI:0914”(association)	0.350
CCDC14	TBC1D31	psi-mi:“MI:0914”(association)	0.350
Pdlim5	HECTD4	psi-mi:“MI:0914”(association)	0.350
MVD	FASN	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
PER2	CIBAR1	psi-mi:“MI:0914”(association)	0.350

BioGRID (66): TTLL5 (Affinity Capture-MS), TTLL5 (Proximity Label-MS), TTLL5 (Proximity Label-MS), TTLL5 (Proximity Label-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS), TTLL5 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PPD8, A1A5Q5, A2A3K4, A4H5X5, A7E379, B2RXH2, C0SUT9, D3ZKV9, F5HB62, O19132, O36371, O54705, O60291, O75164, O94953, P03177, P33802, P35228, Q1HVD1, Q29RJ0, Q3KSQ2, Q3U2K5, Q3UPF5, Q53WJ1, Q5R4R7, Q5R978, Q5RD88, Q5VW22, Q5VWQ0, Q6B0I6, Q6EEF3, Q6EMB2, Q6PI47, Q6X4W1, Q80T69, Q80TL4, Q8BFX3, Q8BW72, Q8CHB8, Q8K3Y6

Diamond homologs: A2APC3, A4Q9E4, A4Q9E5, A4Q9E8, A4Q9F6, A6NNM8, A6PVC2, A8CVX7, B2GUB3, O95922, P0CAZ0, Q0VC71, Q1ECV4, Q23K29, Q23SI8, Q3SXZ7, Q3SZH6, Q4R7H0, Q564U4, Q5PPI9, Q5R978, Q641W7, Q6EEF3, Q6EMB2, Q8CHB8, Q8N841, Q91V51, Q9BWV7, Q9Y4R7, A4Q9F0, A4Q9F1, A4Q9F4, A8X9V4, E9P886, F7E540, H2KZM9, P38160, P38584, Q09647, Q14679

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1153 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	81
Likely pathogenic	27
Uncertain significance	548
Likely benign	386
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071104	NM_015072.5(TTLL5):c.1312G>T (p.Glu438Ter)	Pathogenic
1071881	NM_015072.5(TTLL5):c.1166C>G (p.Ser389Ter)	Pathogenic
1072044	NM_015072.5(TTLL5):c.1258C>T (p.Arg420Ter)	Pathogenic
1076374	NM_015072.5(TTLL5):c.2212C>T (p.Arg738Ter)	Pathogenic
1200580	NM_015072.5(TTLL5):c.264+1G>A	Pathogenic
1363130	NM_015072.5(TTLL5):c.1242del (p.Phe415fs)	Pathogenic
1377263	NM_015072.5(TTLL5):c.3760C>T (p.Gln1254Ter)	Pathogenic
139513	NM_015072.5(TTLL5):c.1586_1589del (p.Glu529fs)	Pathogenic
139514	NM_015072.5(TTLL5):c.401del (p.Leu134fs)	Pathogenic
139515	NM_015072.5(TTLL5):c.3354G>A (p.Trp1118Ter)	Pathogenic
139516	NM_015072.5(TTLL5):c.1627G>T (p.Glu543Ter)	Pathogenic
139517	NM_015072.5(TTLL5):c.1627G>A (p.Glu543Lys)	Pathogenic
1396629	NM_015072.5(TTLL5):c.1666C>T (p.Arg556Ter)	Pathogenic
1401139	NM_015072.5(TTLL5):c.3510_3519del (p.Ala1171fs)	Pathogenic
1401570	NM_015072.5(TTLL5):c.1987C>T (p.Gln663Ter)	Pathogenic
1436956	NM_015072.5(TTLL5):c.2885dup (p.Cys963fs)	Pathogenic
1442426	NM_015072.5(TTLL5):c.3552del (p.Ser1185fs)	Pathogenic
1453329	NM_015072.5(TTLL5):c.1248del (p.Glu416fs)	Pathogenic
1453768	NM_015072.5(TTLL5):c.365_366del (p.Phe122fs)	Pathogenic
1454621	NM_015072.5(TTLL5):c.2641del (p.Tyr881fs)	Pathogenic
1454773	NM_015072.5(TTLL5):c.1186+1del	Pathogenic
1456061	NM_015072.5(TTLL5):c.3579_3583dup (p.Gly1195fs)	Pathogenic
1456225	NM_015072.5(TTLL5):c.2290_2291del (p.Glu764fs)	Pathogenic
1456352	NM_015072.5(TTLL5):c.629dup (p.Tyr210Ter)	Pathogenic
1457257	NM_015072.5(TTLL5):c.3344dup (p.Phe1116fs)	Pathogenic
1460140	NC_000014.8:g.(?76286330)(76286524_?)del	Pathogenic
1460333	NC_000014.8:g.(?76184184)(76201652_?)del	Pathogenic
1921591	NM_015072.5(TTLL5):c.155del (p.Lys52fs)	Pathogenic
1949090	NM_015072.5(TTLL5):c.1738A>T (p.Lys580Ter)	Pathogenic
1966188	NM_015072.5(TTLL5):c.410dup (p.Asn137fs)	Pathogenic

SpliceAI

8804 predictions. Top by Δscore:

Variant	Effect	Δscore
14:75640940:T:TA	acceptor_gain	1.0000
14:75640945:T:TA	acceptor_gain	1.0000
14:75641170:AT:A	acceptor_gain	1.0000
14:75641171:T:G	acceptor_gain	1.0000
14:75641171:T:TA	acceptor_gain	1.0000
14:75641177:TCCA:T	acceptor_loss	1.0000
14:75641178:CCAG:C	acceptor_loss	1.0000
14:75641179:CA:C	acceptor_loss	1.0000
14:75641181:GGT:G	acceptor_gain	1.0000
14:75641294:G:GG	donor_gain	1.0000
14:75641294:G:T	donor_loss	1.0000
14:75641295:TGA:T	donor_loss	1.0000
14:75641296:GAG:G	donor_loss	1.0000
14:75641827:A:AG	acceptor_gain	1.0000
14:75641828:A:G	acceptor_gain	1.0000
14:75641829:T:G	acceptor_gain	1.0000
14:75641833:T:G	acceptor_gain	1.0000
14:75641895:GAAC:G	donor_gain	1.0000
14:75641899:G:GG	donor_gain	1.0000
14:75651769:A:AC	donor_gain	1.0000
14:75651770:C:CC	donor_gain	1.0000
14:75651772:TGCC:T	donor_gain	1.0000
14:75654870:T:TA	donor_gain	1.0000
14:75654875:C:A	donor_gain	1.0000
14:75654881:CATA:C	donor_gain	1.0000
14:75654884:A:AC	donor_gain	1.0000
14:75654885:C:CC	donor_gain	1.0000
14:75654885:CGT:C	donor_gain	1.0000
14:75657535:T:C	acceptor_gain	1.0000
14:75657535:T:TC	acceptor_gain	1.0000

AlphaMissense

8412 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:75681562:T:G	Y67D	1.000
14:75681605:T:C	L81P	1.000
14:75681620:T:C	F86S	1.000
14:75683578:T:C	L98P	1.000
14:75683583:T:A	W100R	1.000
14:75683583:T:C	W100R	1.000
14:75683585:G:C	W100C	1.000
14:75683585:G:T	W100C	1.000
14:75683645:T:A	N120K	1.000
14:75683645:T:G	N120K	1.000
14:75683650:T:C	F122S	1.000
14:75690203:T:C	L128P	1.000
14:75690209:G:C	R130P	1.000
14:75690211:A:C	K131Q	1.000
14:75690211:A:G	K131E	1.000
14:75690213:G:C	K131N	1.000
14:75690213:G:T	K131N	1.000
14:75690221:T:C	L134P	1.000
14:75690239:G:C	R140P	1.000
14:75690289:T:C	F157L	1.000
14:75690291:C:A	F157L	1.000
14:75690291:C:G	F157L	1.000
14:75690317:T:C	F166S	1.000
14:75699214:T:A	W177R	1.000
14:75699214:T:C	W177R	1.000
14:75699218:T:A	I178K	1.000
14:75699218:T:G	I178R	1.000
14:75699221:T:A	V179E	1.000
14:75699223:A:G	K180E	1.000
14:75699225:A:C	K180N	1.000

dbSNP variants (sampled 300 via entrez): RS1000017567 (14:75696971 G>T), RS1000034409 (14:75793013 G>A), RS1000042811 (14:75777735 T>C,G), RS1000043664 (14:75748663 A>G), RS1000044265 (14:75661249 C>T), RS1000048193 (14:75909646 G>A,T), RS1000054785 (14:75822156 T>A), RS1000083339 (14:75926217 C>T), RS1000085224 (14:75837132 T>C), RS1000122070 (14:75880835 G>A), RS1000129078 (14:75778357 T>C), RS1000140485 (14:75787201 T>G), RS1000143034 (14:75770351 T>A), RS1000143456 (14:75724565 A>G), RS1000145729 (14:75935283 G>A)

Disease associations

OMIM: gene MIM:612268 | disease phenotypes: MIM:615860, MIM:120970, MIM:268000, MIM:215500

GenCC curated gene-disease

Disease	Classification	Inheritance
cone-rod dystrophy 19	Definitive	Autosomal recessive
cone-rod dystrophy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
TTLL5-related retinopathy	Definitive	AR

Mondo (7): inherited retinal dystrophy (MONDO:0019118), oligospermia (MONDO:0001913), cone-rod dystrophy 19 (MONDO:0014372), cone-rod dystrophy (MONDO:0015993), optic atrophy (MONDO:0003608), retinitis pigmentosa (MONDO:0019200), central areolar choroidal dystrophy (MONDO:0008982)

Orphanet (4): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cone rod dystrophy (Orphanet:1872), Retinitis pigmentosa (Orphanet:791), Central areolar choroidal dystrophy (Orphanet:75377)

HPO phenotypes

24 total (26 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0003596	Middle age onset
HP:0007641	Dyschromatopsia
HP:0007663	Reduced visual acuity
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007843	Attenuation of retinal blood vessels
HP:0011003	High myopia
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0012508	Metamorphopsia
HP:0030466	Abnormal full-field electroretinogram
HP:0030629	Perifoveal ring of hyperautofluorescence
HP:0030844	Undetectable pattern electroretinogram
HP:0000556	Retinal dystrophy
HP:0000798	Oligozoospermia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001263_4	Height	1.000000e-07
GCST002288_7	Large artery stroke	1.000000e-07
GCST002935_13	Lead levels	3.000000e-06
GCST90000025_545	Appendicular lean mass	8.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D009845	Oligospermia	C12.100.500.430.508; C12.100.750.700.508; C12.200.294.430.508
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression, affects cotreatment	4
trichostatin A	increases expression	2
Benzo(a)pyrene	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
bufotalin	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, increases activity, increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	increases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

281 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT05320536	PHASE4	UNKNOWN	A Clinical Study of Gulingji Capsule in the Treatment of Idiopathic Oligospermia, Asthenia, and Teratozoospermia
NCT06260007	PHASE4	RECRUITING	Efficacy and Safety Study of Products Based on Tribulus Terrestris, L. in Men With Oligospermia
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00440180	PHASE3	TERMINATED	Aromatase Inhibitors in the Treatment of Male Infertility
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01409837	PHASE2	COMPLETED	The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
NCT02234206	PHASE2	COMPLETED	A Clinical Trial to Study the Safety and Efficacy of Chandrakanthi Choornam in Patients With Low Sperm Count
NCT07481370	PHASE2	ENROLLING_BY_INVITATION	Isotretinoin vs hCG for Male Infertility Due to Low or Absent Sperm
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa