TTPA

Summary

TTPA (alpha tocopherol transfer protein, HGNC:12404) is a protein-coding gene on chromosome 8q12.3, encoding Alpha-tocopherol transfer protein (P49638). Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells.

This gene encodes a soluble protein that binds alpha-trocopherol, a form of vitamin E, with high selectivity and affinity. This protein plays an important role in regulating vitamin E levels in the body by transporting vitamin E between membrane vesicles and facilitating the secretion of vitamin E from hepatocytes to circulating lipoproteins. Mutations in this gene cause hereditary vitamin E deficiency (ataxia with vitamin E deficiency, AVED) and retinitis pigmentosa.

Source: NCBI Gene 7274 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial isolated deficiency of vitamin E (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 502 total — 39 pathogenic, 38 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• MANE Select transcript: NM_000370

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12404
Approved symbol	TTPA
Name	alpha tocopherol transfer protein
Location	8q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000137561
Ensembl biotype	protein_coding
OMIM	600415
Entrez	7274

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000260116, ENST00000521138, ENST00000878692, ENST00000878693, ENST00000878694, ENST00000878695, ENST00000878696, ENST00000878697

RefSeq mRNA: 6 — MANE Select: NM_000370 NM_000370, NM_001413414, NM_001413415, NM_001413416, NM_001413417, NM_001413418

CCDS: CCDS6178

Canonical transcript exons

ENST00000260116 — 5 exons

Exon	Start	End
ENSE00000819496	63064206	63064316
ENSE00001201483	63065904	63066097
ENSE00001201488	63072935	63073088
ENSE00001201491	63059488	63061425
ENSE00002100795	63085818	63086053

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 92.95.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0812 / max 236.0676, expressed in 243 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93328	0.9714	221
205208	0.0482	15
93329	0.0456	14
93327	0.0159	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	92.95	gold quality
liver	UBERON:0002107	87.07	gold quality
buccal mucosa cell	CL:0002336	77.33	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.87	gold quality
rectum	UBERON:0001052	74.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.48	silver quality
ventricular zone	UBERON:0003053	71.44	gold quality
nucleus accumbens	UBERON:0001882	65.88	gold quality
caudate nucleus	UBERON:0001873	65.23	gold quality
amygdala	UBERON:0001876	65.04	gold quality
mucosa of transverse colon	UBERON:0004991	63.32	gold quality
putamen	UBERON:0001874	63.26	gold quality
ganglionic eminence	UBERON:0004023	62.19	gold quality
cingulate cortex	UBERON:0003027	61.59	gold quality
anterior cingulate cortex	UBERON:0009835	61.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	60.23	gold quality
transverse colon	UBERON:0001157	60.21	gold quality
prefrontal cortex	UBERON:0000451	59.80	gold quality
hypothalamus	UBERON:0001898	59.40	gold quality
ileal mucosa	UBERON:0000331	59.18	silver quality
right frontal lobe	UBERON:0002810	58.84	gold quality
colonic epithelium	UBERON:0000397	58.43	silver quality
telencephalon	UBERON:0001893	57.44	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	57.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	57.13	gold quality
neocortex	UBERON:0001950	56.97	gold quality
subcutaneous adipose tissue	UBERON:0002190	56.94	gold quality
substantia nigra	UBERON:0002038	56.81	gold quality
embryo	UBERON:0000922	56.47	gold quality
medial globus pallidus	UBERON:0002477	56.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, JUN, NR1H3, NR1I2, TCF3

miRNA regulators (miRDB)

111 targeting TTPA, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3919	99.87	69.45	2489

Literature-anchored findings (GeneRIF, showing 28)

• First case of a mutated form of the TTPA gene in a patient also carrying a spinocerebellar ataxia type 8 expansion. (PMID:12470185)
• crystal structure reveals two conformations (PMID:12899840)
• the positively charged surface of TTPA may serve to orient an interacting protein, which might function to regulate the release of alpha-T through an induced change in conformation of ATTP (PMID:14657365)
• Findings suggest the possibility that ataxia with vitamin E deficiency syndrome (AVED) may not arise from an inability of TTP to bind or to transfer alpha tocopherol, but rather from defects in other activities of the protein. (PMID:15065857)
• Nuclear localization of TTPA in in trophoblast, fetal capillaries’ endothelium and amnion epithelium of human term placentamay represent a novel function of TTPA (PMID:15190938)
• In Ataxia with vitamin E deficiency two TTPA mutations were identified: a truncating mutation in a homozygous patient, and a Gly246Arg missense mutation in a compound heterozygous patient associated with a mild and slowly progressive form of the disease. (PMID:15300460)
• The physiological role of TTP is anchored in its ability to direct vitamin E trafficking from the endocytic compartment to transport vesicles that deliver the vitamin to the site of secretion at the plasma membrane. (PMID:16819822)
• analysis of ligand transfer by the hepatic tocopherol transfer protein (PMID:18458085)
• in first-trimester extravillous trophoblast, syncytiotrophoblast and amniotic epithelium (PMID:18511174)
• The vitamin E deficiency with hereditary motor neuropathy was found to be homozygous for a 513insTT mutation in exon 3 of the alpha-tocopherol transfer protein gene. (PMID:18984846)
• Total deletion of the TTPA gene is expected to be associated with severe phenotype in AVED patients. (PMID:19102053)
• Genetic variation in TTPA and SEC14L2 is associated with serum alpha-tocopherol but does not have a direct effect on prostate cancer when vitamin E is administered. (PMID:19190344)
• Hydrophobic features of alpha-TTP dominating the binding energy between protein and membrane. (PMID:19458973)
• Data show that reduction (“knockdown”) of tocopherol transfer protein (TTP) expression resulted in resistance to the vitamin E. (PMID:20826775)
• Substitution of residues in helices A8 (F165A and F169A) and A10 (I202A, V206A and M209A) decreased the rate of intermembrane ligand transfer as well as protein adsorption to phospholipid bilayers. (PMID:21110980)
• study demonstrated that alpha -TTP can be upregulated in case of oxidative stress in BeWo trophoblast cells; speculate that possibly, alpha -TTP is notonly involved in normal pregnancy, but also in cases of pregnancy disorders with intense oxidative stress (PMID:22752767)
• Single-nucleotide polymorphisms that are commonly found in healthy humans dramatically affect promoter activity of the TTPA gene. (PMID:23079030)
• The crystal structure of the alpha-TTP-phosphatidylinositol phosphates (PIPs) complex revealed that the familial vitamin E deficiency-related arginine residues interacted with phosphate groups of the PIPs and that the PIPs binding caused the lid of the alpha-tocopherol-binding pocket to open. (PMID:23599266)
• These findings provide the basis for a proposed mechanistic model that describes TTP-facilitated trafficking of alpha-tocopherol through hepatocytes. (PMID:27307040)
• Current results show that alphaTTP plays a role in endometrial carcinoma. Possibly endometrial cancer cells attempt to protect themselves from increasing oxidative stress by up-regulating alphaTTP. (PMID:28213729)
• Data show that, upon binding to its substrate, alpha-TTP acquires tendency to aggregation into thermodynamically stable high molecular weight oligomers with spheroidal particle formed by 24 protein monomers. Oligomerization is triggered by refolding of the N-terminus. These same oligomers are efficiently transported through an endothelial barrier and not through an epithelial one. (PMID:28694484)
• Authors show that a novel interaction between TTP and the CCR4-NOT subunit, CNOT9, is required for recruitment of the deadenylase complex. In addition to CNOT1, CNOT9 is now included in the identified CCR4-NOT subunits shown to interact with TTP. (PMID:29291391)
• alphaTTP does not appear to regulate the uptake and intracellular localization of different vitamin E congeners in cultured liver cells. (PMID:30098456)
• Low TTP expression is associated with liver fibrosis. (PMID:30226813)
• alpha-Tocopherol Transfer Protein Enhances alpha-Tocopherol Protective Effects in Lung A549 Cells. (PMID:32469275)
• alpha-Tocopherol transfer protein (alpha-TTP). (PMID:34563650)
• The tocopherol transfer protein mediates vitamin E trafficking between cerebellar astrocytes and neurons. (PMID:35150738)
• Genetic heterogeneity within a consanguineous family involving TTPA and SETX genes. (PMID:38109176)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttpa	ENSDARG00000027584
mus_musculus	Ttpa	ENSMUSG00000073988
rattus_norvegicus	Ttpa	ENSRNOG00000007139
drosophila_melanogaster	CG10026	FBGN0032785
caenorhabditis_elegans		WBGENE00007925

Paralogs (6): SEC14L2 (ENSG00000100003), SEC14L3 (ENSG00000100012), SEC14L5 (ENSG00000103184), SEC14L1 (ENSG00000129657), SEC14L4 (ENSG00000133488), SEC14L6 (ENSG00000214491)

Protein

Protein identifiers

Alpha-tocopherol transfer protein — P49638 (reviewed: P49638)

All UniProt accessions (1): P49638

UniProt curated annotations — full annotation on UniProt →

Function. Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells. Binds both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate; the resulting conformation change is important for the release of the bound alpha-tocopherol.

Subunit / interactions. Monomer and homotetramer. Phosphatidylinositol 4,5-bisphosphate binding induces the formation of homotetramers. Phosphatidylinositol 3,4-bisphosphate is less efficient in inducing tetramerization.

Subcellular location. Cytoplasm.

Disease relevance. Ataxia with vitamin E deficiency (AVED) [MIM:277460] An autosomal recessive disease characterized by undetectable or markedly reduced plasma levels of vitamin E, spinocerebellar degeneration, ataxia, areflexia and proprioception loss. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (6): NP_000361, NP_001400343, NP_001400344, NP_001400345, NP_001400346, NP_001400347 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001251	CRAL-TRIO_dom	Domain
IPR011074	CRAL/TRIO_N_dom	Domain
IPR036273	CRAL/TRIO_N_dom_sf	Homologous_superfamily
IPR036865	CRAL-TRIO_dom_sf	Homologous_superfamily

Pfam: PF00650, PF03765

UniProt features (50 total): helix 21, sequence variant 8, strand 7, binding site 6, turn 3, chain 1, domain 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1R5L	X-RAY DIFFRACTION	1.5
1OIZ	X-RAY DIFFRACTION	1.88
1OIP	X-RAY DIFFRACTION	1.95
6ZPD	X-RAY DIFFRACTION	2.24
5MUE	X-RAY DIFFRACTION	2.4
5MUG	X-RAY DIFFRACTION	2.42

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49638-F1	94.44	0.93

Functional residue map

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

Ligand- & substrate-binding residues (6): 185; 187; 190–192; 208–211; 217; 221

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8877627	Vitamin E transport

MSigDB gene sets: 219 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, NIKOLSKY_BREAST_CANCER_8Q12_Q22_AMPLICON, GOBP_VITAMIN_TRANSPORT, GOBP_LIPID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_EMBRYO_DEVELOPMENT, GOBP_MEMBRANE_ORGANIZATION, GOBP_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_PLACENTA_DEVELOPMENT, GOBP_LIPID_LOCALIZATION, GOBP_EMBRYONIC_ORGAN_DEVELOPMENT

GO Biological Process (9): embryonic placenta development (GO:0001892), lipid metabolic process (GO:0006629), response to toxic substance (GO:0009636), vitamin E metabolic process (GO:0042360), vitamin transport (GO:0051180), negative regulation of establishment of blood-brain barrier (GO:0090212), intermembrane lipid transfer (GO:0120009), positive regulation of amyloid-beta clearance (GO:1900223), placenta development (GO:0001890)

GO Molecular Function (7): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), vitamin E binding (GO:0008431), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), lipid transfer activity (GO:0120013), phosphatidylinositol bisphosphate binding (GO:1902936), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (3): late endosome (GO:0005770), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of fat-soluble vitamins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol bisphosphate binding	2
binding	2
cellular anatomical structure	2
in utero embryonic development	1
placenta development	1
embryonic organ development	1
primary metabolic process	1
response to chemical	1
metabolic process	1
transport	1
negative regulation of cell development	1
establishment of blood-brain barrier	1
regulation of establishment of blood-brain barrier	1
lipid transport	1
membrane organization	1
positive regulation of multicellular organismal process	1
amyloid-beta clearance	1
regulation of amyloid-beta clearance	1
animal organ development	1
phosphatidylinositol phosphate binding	1
vitamin binding	1
heterocyclic compound binding	1
transporter activity	1
lipid carrier activity	1
intermembrane lipid transfer	1
anion binding	1
endosome	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTPA	ATCAY	Q86WG3	912
TTPA	PRUNE2	Q8WUY3	768
TTPA	SLC6A11	P48066	744
TTPA	BNIP2	Q12982	736
TTPA	FXN	Q16595	736
TTPA	TWNK	Q96RR1	694
TTPA	CACNA1A	P78510	656
TTPA	EIF3K	Q9UBQ5	648
TTPA	CYP4F2	P78329	592
TTPA	SLC23A2	Q9UGH3	577
TTPA	MBNL1	Q9NR56	548
TTPA	APTX	Q7Z2E3	540
TTPA	CELF1	Q92879	506
TTPA	SIL1	Q9H173	506
TTPA	APOE	P02649	494

IntAct

134 interactions, top by confidence:

A	B	Type	Score
TTPA	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
TTPA	REEP2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	ARMC12	psi-mi:“MI:0915”(physical association)	0.560
TTPA	SCAMP5	psi-mi:“MI:0915”(physical association)	0.560
TTPA	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	TTPA	psi-mi:“MI:0915”(physical association)	0.560
TTPA	KRTAP12-2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	MAL2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	BIRC7	psi-mi:“MI:0915”(physical association)	0.560
TTPA	TPD52	psi-mi:“MI:0915”(physical association)	0.560
TTPA	KRTAP12-3	psi-mi:“MI:0915”(physical association)	0.560
TTPA	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
TTPA	KRTAP2-4	psi-mi:“MI:0915”(physical association)	0.560
TTPA	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	ARFIP2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	DGAT2L6	psi-mi:“MI:0915”(physical association)	0.560
TTPA	CISD2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	FADS6	psi-mi:“MI:0915”(physical association)	0.560
SCAMP1	TTPA	psi-mi:“MI:0915”(physical association)	0.560
TTPA	FAM114A2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	RPRM	psi-mi:“MI:0915”(physical association)	0.560
SYNGR3	TTPA	psi-mi:“MI:0915”(physical association)	0.560
FAM25C	TTPA	psi-mi:“MI:0915”(physical association)	0.560
TTPA	SAR1A	psi-mi:“MI:0915”(physical association)	0.560
TTPA	DHODH	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (50): CMTM5 (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid), TTPA (Two-hybrid)

ESM2 similar proteins: A0A3L7I2I8, A6JFQ6, A6JUQ6, A7MBL8, E1C3P4, O08874, O60733, O70291, O94806, P41034, P49638, P97570, P97819, Q02384, Q07889, Q07890, Q16513, Q2KIX2, Q3LAC4, Q4R678, Q5E9G6, Q5F361, Q5M7E1, Q5RCA6, Q5SPP0, Q5SYC1, Q641K1, Q66H63, Q6NRC7, Q70Z35, Q8BG92, Q8BM85, Q8BWP5, Q8BWW9, Q8CA95, Q8IUQ0, Q8K1Y2, Q8NHP6, Q8TEA7, Q8W4D4

Diamond homologs: A6JFQ6, A6JUQ6, E1C1U1, P10123, P12271, P41034, P49638, Q19895, Q5M7E1, Q5RCA6, Q5RFR0, Q5SPP0, Q5SYC1, Q8BG92, Q8BWP5, Q8IUQ0, Q95KF7, Q9BTX7, Q9D3D0, Q9D4C9, Q9Z275, P53989, P49193, A6ZQI5, A8Y5H7, B5MCN3, F4HP88, F4IHJ0, F4J7S8, O17907, O43304, O76054, P47008, P58875, Q03606, Q0V9N0, Q10137, Q29JQ0, Q6FQI6, Q7PWB1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	38
Uncertain significance	177
Likely benign	190
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027489	NM_000370.3(TTPA):c.553-1G>T	Pathogenic
1070113	NM_000370.3(TTPA):c.727del (p.Leu243fs)	Pathogenic
1074404	NM_000370.3(TTPA):c.375_412dup (p.Ile138delinsLysPheLeuGlnLeuMetThrTyrPheGluTer)	Pathogenic
1074758	NM_000370.3(TTPA):c.178dup (p.Asp60fs)	Pathogenic
1299121	NM_000370.3(TTPA):c.300C>A (p.Tyr100Ter)	Pathogenic
1412594	NM_000370.3(TTPA):c.235G>T (p.Glu79Ter)	Pathogenic
1451654	NM_000370.3(TTPA):c.290del (p.Lys97fs)	Pathogenic
1452965	NM_000370.3(TTPA):c.421G>T (p.Glu141Ter)	Pathogenic
1454920	NC_000008.10:g.(?63985484)(63985657_?)del	Pathogenic
1457270	NM_000370.3(TTPA):c.242del (p.Pro81fs)	Pathogenic
1459425	NM_000370.3(TTPA):c.218_219dup (p.Tyr74fs)	Pathogenic
188951	NM_000370.3(TTPA):c.487del (p.Trp163fs)	Pathogenic
1976696	NM_000370.3(TTPA):c.85del (p.Ala29fs)	Pathogenic
2002112	NM_000370.3(TTPA):c.58dup (p.His20fs)	Pathogenic
2019084	NM_000370.3(TTPA):c.85_86insGGGCGCTGCGGCGCCGGGCCCGG (p.Ala29fs)	Pathogenic
2020207	NM_000370.3(TTPA):c.266del (p.Pro89fs)	Pathogenic
2054578	NM_000370.3(TTPA):c.433C>T (p.Gln145Ter)	Pathogenic
2422971	NC_000008.10:g.(?63998357)(63998581_?)del	Pathogenic
267261	NM_000370.3(TTPA):c.205-1G>T	Pathogenic
2692644	NM_000370.3(TTPA):c.26C>A (p.Ser9Ter)	Pathogenic
2703680	NM_000370.3(TTPA):c.92_102del (p.Leu31fs)	Pathogenic
2772927	NM_000370.3(TTPA):c.222T>A (p.Tyr74Ter)	Pathogenic
2788836	NM_000370.3(TTPA):c.83_105dup (p.Arg36fs)	Pathogenic
2813619	NM_000370.3(TTPA):c.292del (p.Ala98fs)	Pathogenic
2836483	NM_000370.3(TTPA):c.420del (p.Glu141fs)	Pathogenic
2863968	NM_000370.3(TTPA):c.376del (p.Val126fs)	Pathogenic
2873865	NM_000370.3(TTPA):c.372del (p.Val126fs)	Pathogenic
3245551	NC_000008.10:g.(?63973811)(63998581_?)del	Pathogenic
370407	NM_000370.3(TTPA):c.205-1G>C	Pathogenic
448839	NM_000370.3(TTPA):c.366G>A (p.Trp122Ter)	Pathogenic

SpliceAI

830 predictions. Top by Δscore:

Variant	Effect	Δscore
8:63065899:TTTAC:T	donor_loss	1.0000
8:63065900:TTAC:T	donor_loss	1.0000
8:63065901:TA:T	donor_loss	1.0000
8:63065902:A:AC	donor_gain	1.0000
8:63065903:C:CC	donor_gain	1.0000
8:63065903:C:CT	donor_loss	1.0000
8:63066095:GTG:G	acceptor_gain	1.0000
8:63066095:GTGC:G	acceptor_loss	1.0000
8:63066097:GCTA:G	acceptor_loss	1.0000
8:63066098:C:CA	acceptor_loss	1.0000
8:63066098:C:CC	acceptor_gain	1.0000
8:63085812:GCTTA:G	donor_loss	1.0000
8:63085813:CTTA:C	donor_loss	1.0000
8:63085814:TTA:T	donor_loss	1.0000
8:63085815:TA:T	donor_loss	1.0000
8:63085816:AC:A	donor_gain	1.0000
8:63085816:ACCCG:A	donor_gain	1.0000
8:63085817:CC:C	donor_gain	1.0000
8:63085817:CCCG:C	donor_gain	1.0000
8:63085817:CCCGC:C	donor_gain	1.0000
8:63064200:AC:A	donor_loss	0.9900
8:63064201:CT:C	donor_loss	0.9900
8:63064202:TCACC:T	donor_loss	0.9900
8:63064203:CACCC:C	donor_loss	0.9900
8:63064204:A:C	donor_loss	0.9900
8:63064204:AC:A	donor_gain	0.9900
8:63064205:C:CA	donor_loss	0.9900
8:63064205:CC:C	donor_gain	0.9900
8:63064242:CA:C	acceptor_gain	0.9900
8:63064316:CCTTT:C	acceptor_gain	0.9900

AlphaMissense

1819 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:63066048:A:C	S136R	0.999
8:63066048:A:T	S136R	0.999
8:63066050:T:G	S136R	0.999
8:63064207:C:G	R221P	0.998
8:63065929:G:T	A176D	0.998
8:63065998:C:T	G153E	0.998
8:63066092:A:G	W122R	0.998
8:63066092:A:T	W122R	0.998
8:63064228:A:G	L214P	0.997
8:63065998:C:A	G153V	0.997
8:63085857:G:C	F55L	0.997
8:63085857:G:T	F55L	0.997
8:63085859:A:G	F55L	0.997
8:63061314:A:G	W259R	0.996
8:63061314:A:T	W259R	0.996
8:63065953:G:T	A168D	0.996
8:63065969:A:G	W163R	0.996
8:63065969:A:T	W163R	0.996
8:63065977:A:G	L160P	0.996
8:63064252:A:T	V206D	0.995
8:63064306:G:T	P188Q	0.995
8:63065917:G:T	A180D	0.995
8:63066055:C:G	R134P	0.995
8:63066046:A:G	L137P	0.994
8:63072952:A:T	V114D	0.993
8:63073084:A:G	L70P	0.993
8:63064306:G:C	P188R	0.992
8:63065999:C:G	G153R	0.992
8:63065999:C:T	G153R	0.992
8:63066031:A:G	L142P	0.992

dbSNP variants (sampled 300 via entrez): RS1000063911 (8:63083364 A>G), RS1000387118 (8:63069293 A>T), RS1000464693 (8:63082604 A>G), RS1000527478 (8:63078941 A>G), RS1000555079 (8:63078733 G>A), RS1000759000 (8:63073103 T>C), RS1000854271 (8:63059243 G>A), RS1000882314 (8:63075010 C>A,G), RS1000992928 (8:63067455 A>G), RS1001000970 (8:63085264 C>G,T), RS1001069325 (8:63081034 C>T), RS1001087979 (8:63073473 C>T), RS1001474632 (8:63084964 C>A,T), RS1001560018 (8:63080051 C>A,T), RS1001590052 (8:63070683 G>A,T)

Disease associations

OMIM: gene MIM:600415 | disease phenotypes: MIM:277460, MIM:214800

GenCC curated gene-disease

Disease	Classification	Inheritance
familial isolated deficiency of vitamin E	Definitive	Autosomal recessive

Mondo (4): familial isolated deficiency of vitamin E (MONDO:0010188), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), CHD7-related CHARGE syndrome (MONDO:1010178)

Orphanet (2): Ataxia with vitamin E deficiency (Orphanet:96), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000505	Visual impairment
HP:0000580	Pigmentary retinopathy
HP:0000639	Nystagmus
HP:0000649	Abnormality of visual evoked potentials
HP:0000662	Nyctalopia
HP:0000763	Sensory neuropathy
HP:0000819	Diabetes mellitus
HP:0001114	Xanthelasma
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001639	Hypertrophic cardiomyopathy
HP:0001761	Pes cavus
HP:0002073	Progressive cerebellar ataxia
HP:0002075	Dysdiadochokinesis
HP:0002155	Hypertriglyceridemia
HP:0002167	Abnormal speech pattern
HP:0002312	Clumsiness
HP:0002376	Developmental regression
HP:0002403	Positive Romberg sign

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST011397_1	Response to esketamine (responder status) in treatment resistant depression	8.000000e-07
GCST011398_27	Response to esketamine in treatment resistant depression	6.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009748	response to ketamine

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
C535393	Ataxia with vitamin E deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3308919 (SINGLE PROTEIN)

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 8 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.03	Kd	94	nM	CHEMBL5420235
6.44	Kd	360	nM	CHEMBL247483
5.95	Kd	1130	nM	CHEMBL595636
5.66	Kd	2190	nM	CHEMBL391747
5.62	Kd	2420	nM	ALPHA-TOCOPHEROL
5.62	Kd	2390	nM	CHEMBL594042

PubChem BioAssay actives

6 with measured affinity, of 15 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R)-2-[8-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)octyl]-2,5,7,8-tetramethyl-3,4-dihydrochromen-6-ol	1985085: Binding affinity to human alpha-TTP assessed as dissociation constant incubated for 25 to 40 mins by fluorescence based assay	kd	0.0940	uM
[2,7,8-trimethyl-5-(nitrooxymethyl)-2-(4,8,12-trimethyltridecyl)-3,4-dihydrochromen-6-yl] acetate	454510: Displacement of NBD-Toc from human recombinant alphaTTP	kd	0.3600	uM
[6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydrochromen-5-yl]methyl nitrate	454510: Displacement of NBD-Toc from human recombinant alphaTTP	kd	1.1300	uM
3-[[4-(benzenesulfonyl)-5-oxido-1,2,5-oxadiazol-5-ium-3-yl]oxy]propyl 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carboxylate	454510: Displacement of NBD-Toc from human recombinant alphaTTP	kd	2.1900	uM
2-[[4-(benzenesulfonyl)-5-oxido-1,2,5-oxadiazol-5-ium-3-yl]oxy]ethyl 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carboxylate	454510: Displacement of NBD-Toc from human recombinant alphaTTP	kd	2.3900	uM
(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-ol	454510: Displacement of NBD-Toc from human recombinant alphaTTP	kd	2.4200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Vitamin E	decreases abundance, increases response to substance	4
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Valproic Acid	decreases expression, decreases methylation, increases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
sotorasib	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
methylparaben	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
nickel sulfate	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
abrine	decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Phenobarbital	increases expression	1
Tobacco Smoke Pollution	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1067320	Binding	Displacement of NBD-Toc from human recombinant alphaTTP at 15 uM	Interaction studies between human alpha-tocopherol transfer protein and nitric oxide donor tocopherol analogues with LDL-protective activity. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_M989	GM01960	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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]
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)
NCT06375239	Not specified	RECRUITING	Observational Study to Assess Endpoint Operational Feasibility & Measurement Properties in Patients with Retinal Degeneration