ACOT8

Summary

ACOT8 (acyl-CoA thioesterase 8, HGNC:15919) is a protein-coding gene on chromosome 20q13.12, encoding Acyl-coenzyme A thioesterase 8 (O14734). Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels.

The protein encoded by this gene is a peroxisomal thioesterase that appears to be involved more in the oxidation of fatty acids rather than in their formation. The encoded protein can bind to the human immunodeficiency virus-1 protein Nef, and mediate Nef-induced down-regulation of CD4 in T-cells.

Source: NCBI Gene 10005 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 64 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_005469

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15919
Approved symbol	ACOT8
Name	acyl-CoA thioesterase 8
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	hACTE-III, hTE, PTE-2, NAP1
Ensembl gene	ENSG00000101473
Ensembl biotype	protein_coding
OMIM	608123
Entrez	10005

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000217455, ENST00000426915, ENST00000457981, ENST00000461272, ENST00000481938, ENST00000483141, ENST00000484783, ENST00000484975, ENST00000486165, ENST00000487205, ENST00000488679, ENST00000493118, ENST00000652771, ENST00000852115, ENST00000933252, ENST00000933253, ENST00000933254

RefSeq mRNA: 1 — MANE Select: NM_005469 NM_005469

CCDS: CCDS13378

Canonical transcript exons

ENST00000217455 — 6 exons

Exon	Start	End
ENSE00001817842	45841721	45841956
ENSE00001905512	45857188	45857392
ENSE00003477516	45848450	45848675
ENSE00003487486	45844263	45844420
ENSE00003492850	45855159	45855292
ENSE00003660763	45843527	45843721

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.3590 / max 162.8225, expressed in 1819 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187494	26.3590	1819

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	96.23	gold quality
right adrenal gland	UBERON:0001233	94.05	gold quality
right adrenal gland cortex	UBERON:0035827	93.93	gold quality
prefrontal cortex	UBERON:0000451	93.70	gold quality
left adrenal gland	UBERON:0001234	93.30	gold quality
left adrenal gland cortex	UBERON:0035825	93.18	gold quality
right frontal lobe	UBERON:0002810	93.05	gold quality
cingulate cortex	UBERON:0003027	92.97	gold quality
anterior cingulate cortex	UBERON:0009835	92.93	gold quality
apex of heart	UBERON:0002098	92.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.81	gold quality
nucleus accumbens	UBERON:0001882	92.15	gold quality
adrenal cortex	UBERON:0001235	92.07	gold quality
caudate nucleus	UBERON:0001873	91.93	gold quality
granulocyte	CL:0000094	91.60	gold quality
amygdala	UBERON:0001876	91.53	gold quality
adrenal gland	UBERON:0002369	91.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.29	gold quality
putamen	UBERON:0001874	91.28	gold quality
adrenal tissue	UBERON:0018303	91.02	gold quality
right atrium auricular region	UBERON:0006631	90.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.94	gold quality
gastrocnemius	UBERON:0001388	90.70	gold quality
body of stomach	UBERON:0001161	90.69	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.67	gold quality
skin of leg	UBERON:0001511	90.65	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.54	gold quality
frontal cortex	UBERON:0001870	90.50	gold quality
neocortex	UBERON:0001950	90.50	gold quality
lower esophagus mucosa	UBERON:0035834	90.49	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.66
E-HCAD-5	no	2.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SMARCA1

Literature-anchored findings (GeneRIF, showing 5)

• ACOT4 and ACOT8 are responsible for the termination of beta-oxidation of dicarboxylic acids of medium-chain length with the concomitant release of the corresponding free acids (PMID:16141203)
• SREBP2 modulates brain palmitoyl-coa hydrolase gene transcription. (PMID:16335799)
• An isoform of long-chain acyl-CoA hydrolase may be responsible for the nafamostat hydrolysis in human liver cytosol. (PMID:17624024)
• Acyl-CoA thioesterase 8 is a specific protein related to nodal metastasis and prognosis of lung adenocarcinoma. (PMID:23540296)
• In summary, lipolytic enzyme ACOT8 is frequently upregulated in HCC clinical specimens. More importantly, ACOT8 silencing leads to inhibition of cell growth in HCC in vitro. (PMID:24788990)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	acot8	ENSDARG00000014138
mus_musculus	Acot8	ENSMUSG00000017307
rattus_norvegicus	Acot8	ENSRNOG00000015187
caenorhabditis_elegans		WBGENE00015887
caenorhabditis_elegans		WBGENE00015889
caenorhabditis_elegans		WBGENE00016511
caenorhabditis_elegans		WBGENE00017048
caenorhabditis_elegans		WBGENE00017781

Protein

Protein identifiers

Acyl-coenzyme A thioesterase 8 — O14734 (reviewed: O14734)

Alternative names: Choloyl-coenzyme A thioesterase, HIV-Nef-associated acyl-CoA thioesterase, Peroxisomal acyl-CoA thioesterase 2, Peroxisomal acyl-coenzyme A thioester hydrolase 1, Peroxisomal long-chain acyl-CoA thioesterase 1, Thioesterase II

All UniProt accessions (9): O14734, A0A494C0N6, E9PIS4, E9PJN0, E9PRD4, F6VBM3, H0Y698, H7C5A7, Q9BR14

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. Displays no strong substrate specificity with respect to the carboxylic acid moiety of Acyl-CoAs. Hydrolyzes medium length (C2 to C20) straight-chain, saturated and unsaturated acyl-CoAS but is inactive towards substrates with longer aliphatic chains. Moreover, it catalyzes the hydrolysis of CoA esters of bile acids, such as choloyl-CoA and chenodeoxycholoyl-CoA and competes with bile acid CoA:amino acid N-acyltransferase (BAAT). Is also able to hydrolyze CoA esters of dicarboxylic acids. It is involved in the metabolic regulation of peroxisome proliferation. (Microbial infection) May mediate Nef-induced down-regulation of CD4 cell-surface expression.

Subunit / interactions. Homodimer. (Microbial infection) Interacts with human immunodeficiency virus (HIV-1) Nef (via middle region); this interaction enhances ACOT8 Acyl-CoA thioesterase activity and occurs in a Nef myristoylation-independent manner. According to a second report, the interaction with HIV-1 Nef occurs in a Nef myristoylation-independent manner but does not enhance ACOT8 Acyl-CoA thioesterase activity.

Subcellular location. Peroxisome matrix.

Tissue specificity. Detected in a T-cell line (at protein level). Ubiquitous.

Activity regulation. Inhibited by CoASH (IC(50)=10-15 uM). Also inhibited by cysteine-reactive agents.

Induction. Regulated by peroxisome proliferator (such as Clofibrate), via the peroxisome proliferator-activated receptors (PPARs).

Pathway. Lipid metabolism; fatty acid metabolism.

Similarity. Belongs to the C/M/P thioester hydrolase family.

RefSeq proteins (1): NP_005460* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003703	Acyl_CoA_thio	Family
IPR029069	HotDog_dom_sf	Homologous_superfamily
IPR042171	Acyl-CoA_hotdog	Homologous_superfamily
IPR049449	TesB_ACOT8-like_N	Domain
IPR049450	ACOT8-like_C	Domain

Pfam: PF13622, PF20789

Enzyme classification (BRENDA):

• EC 3.1.2.2 — palmitoyl-CoA hydrolase (BRENDA: 40 organisms, 184 substrates, 159 inhibitors, 142 Km, 46 kcat entries)
• EC 3.1.2.20 — acyl-CoA hydrolase (BRENDA: 47 organisms, 273 substrates, 173 inhibitors, 271 Km, 184 kcat entries)

Substrate kinetics (BRENDA)

111 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HEXADECANOYL-COA	—	26
HEXADECANOYL-COA	—	25
PALMITOYL-COA	0.0024–33	14
MYRISTOYL-COA	0.0025–0.0228	13
DODECANOYL-COA	0.0018–0.325	12
3-HYDROXYPHENYLACETYL-COA	0.0037–0.9	11
LAUROYL-COA	0.0385–0.185	10
OLEOYL-COA	0.0014–0.0274	10
ARACHIDONOYL-COA	0.0004–0.02	9
DODECANOYL-COA	0.0018–0.325	9
LAUROYL-COA	0.0035–0.0275	9
PALMITOLEOYL-COA	0.0014–0.058	9
OLEOYL-COA	0.0014–0.0088	8
TETRADECANOYL-COA	0.0016–0.024	8
2,3-DIHYDROXYBENZOYL-COA	0.0375–1.42	7

Catalyzed reactions (Rhea), 12 shown:

• succinyl-CoA + H2O = succinate + CoA + H(+) (RHEA:11516)
• choloyl-CoA + H2O = cholate + CoA + H(+) (RHEA:14541)
• acetoacetyl-CoA + H2O = acetoacetate + CoA + H(+) (RHEA:15673)
• (3S)-3-hydroxy-3-methylglutaryl-CoA + H2O = 3-hydroxy-3-methylglutarate + CoA + H(+) (RHEA:16305)
• hexadecanoyl-CoA + H2O = hexadecanoate + CoA + H(+) (RHEA:16645)
• acetyl-CoA + H2O = acetate + CoA + H(+) (RHEA:20289)
• dodecanoyl-CoA + H2O = dodecanoate + CoA + H(+) (RHEA:30135)
• octadecanoyl-CoA + H2O = octadecanoate + CoA + H(+) (RHEA:30139)
• octanoyl-CoA + H2O = octanoate + CoA + H(+) (RHEA:30143)
• chenodeoxycholoyl-CoA + H2O = chenodeoxycholate + CoA + H(+) (RHEA:31511)
• decanoyl-CoA + H2O = decanoate + CoA + H(+) (RHEA:40059)
• propanoyl-CoA + H2O = propanoate + CoA + H(+) (RHEA:40103)

UniProt features (9 total): active site 3, sequence conflict 2, chain 1, region of interest 1, short sequence motif 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14734-F1	88.58	0.70

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 (3): 232 (charge relay system); 254 (charge relay system); 304 (charge relay system)

Mutagenesis-validated functional residues (1):

Position	Phenotype
78	reduces acyl-coa thioesterase activity and peroxisome proliferation.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-193368	Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
R-HSA-2046106	alpha-linolenic acid (ALA) metabolism
R-HSA-389887	Beta-oxidation of pristanoyl-CoA
R-HSA-390247	Beta-oxidation of very long chain fatty acids
R-HSA-9033241	Peroxisomal protein import
R-HSA-1430728	Metabolism
R-HSA-192105	Synthesis of bile acids and bile salts
R-HSA-194068	Bile acid and bile salt metabolism
R-HSA-2046104	alpha-linolenic (omega3) and linoleic (omega6) acid metabolism
R-HSA-390918	Peroxisomal lipid metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids
R-HSA-8978868	Fatty acid metabolism
R-HSA-9609507	Protein localization

MSigDB gene sets: 199 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GGGTGGRR_PAX4_03, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, COUP_01, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_BILE_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS

GO Biological Process (14): unsaturated fatty acid biosynthetic process (GO:0006636), acyl-CoA metabolic process (GO:0006637), bile acid biosynthetic process (GO:0006699), fatty acid catabolic process (GO:0009062), negative regulation of glycoprotein biosynthetic process (GO:0010561), peroxisome fission (GO:0016559), fatty acid beta-oxidation using acyl-CoA oxidase (GO:0033540), alpha-linolenic acid metabolic process (GO:0036109), long-chain fatty acid biosynthetic process (GO:0042759), dicarboxylic acid catabolic process (GO:0043649), fatty acid derivative biosynthetic process (GO:1901570), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), peroxisome organization (GO:0007031)

GO Molecular Function (12): acetyl-CoA hydrolase activity (GO:0003986), succinyl-CoA hydrolase activity (GO:0004778), acyl-CoA hydrolase activity (GO:0016289), choloyl-CoA hydrolase activity (GO:0033882), acetoacetyl-CoA hydrolase activity (GO:0047603), fatty acyl-CoA hydrolase activity (GO:0047617), hydroxymethylglutaryl-CoA hydrolase activity (GO:0047994), carboxylic ester hydrolase activity (GO:0052689), medium-chain fatty acyl-CoA hydrolase activity (GO:0052815), long-chain fatty acyl-CoA hydrolase activity (GO:0052816), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): peroxisomal matrix (GO:0005782), cytosol (GO:0005829), peroxisome (GO:0005777)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Peroxisomal lipid metabolism	2
Fatty acid metabolism	2
Metabolism of lipids	2
Synthesis of bile acids and bile salts	1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1
Protein localization	1
Bile acid and bile salt metabolism	1
Metabolism of steroids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
acyl-CoA hydrolase activity	6
fatty acid biosynthetic process	2
unsaturated fatty acid metabolic process	2
long-chain fatty acid metabolic process	2
fatty acyl-CoA hydrolase activity	2
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
bile acid metabolic process	1
monocarboxylic acid biosynthetic process	1
fatty acid metabolic process	1
lipid catabolic process	1
monocarboxylic acid catabolic process	1
glycoprotein biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regulation of glycoprotein biosynthetic process	1
negative regulation of glycoprotein metabolic process	1
peroxisome organization	1
organelle fission	1
fatty acid beta-oxidation	1
olefinic compound metabolic process	1
dicarboxylic acid metabolic process	1
carboxylic acid catabolic process	1
lipid biosynthetic process	1
fatty acid derivative metabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
organelle organization	1
thiolester hydrolase activity	1
deacylase activity	1
hydrolase activity, acting on ester bonds	1
binding	1
catalytic activity	1
peroxisome	1
microbody lumen	1
cytoplasm	1
cellular anatomical structure	1
microbody	1

Protein interactions and networks

STRING

1660 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACOT8	ACOT2	P49753	957
ACOT8	ACOT1	Q86TX2	951
ACOT8	PPARA	Q07869	799
ACOT8	ACOT13	Q9NPJ3	710
ACOT8	ACOT9	Q9Y305	703
ACOT8	ACOT4	Q8N9L9	698
ACOT8	ACOT12	Q8WYK0	656
ACOT8	ACOT6	Q3I5F7	640
ACOT8	ACOT7	O00154	608
ACOT8	ACOT11	Q8WXI4	607
ACOT8	ECH1	Q13011	556
ACOT8	ACOX2	Q99424	543
ACOT8	ACOX1	Q15067	520
ACOT8	PPARD	Q03181	514
ACOT8	ECI2	O75521	511

IntAct

82 interactions, top by confidence:

A	B	Type	Score
ACOT8	nef	psi-mi:“MI:0915”(physical association)	0.710
nef	ACOT8	psi-mi:“MI:0914”(association)	0.710
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
PTPN3	ACOT8	psi-mi:“MI:0914”(association)	0.590
ACOT8	MAST1	psi-mi:“MI:0407”(direct interaction)	0.590
ACOT8	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.590
PEX5	ACOT8	psi-mi:“MI:0915”(physical association)	0.560
REL	ACOT8	psi-mi:“MI:0915”(physical association)	0.560
ACOT8	REL	psi-mi:“MI:0915”(physical association)	0.560
P4HA3	ACOT8	psi-mi:“MI:0915”(physical association)	0.560
	ACOT8	psi-mi:“MI:0915”(physical association)	0.560
ACOT8	P4HA3	psi-mi:“MI:0915”(physical association)	0.560
ACOT8	COA7	psi-mi:“MI:0915”(physical association)	0.560
ACOT8	PML	psi-mi:“MI:0914”(association)	0.530
ACOT8	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
SNX27	ACOT8	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT8	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT8	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT8	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (84): ACOT8 (Two-hybrid), ACOT8 (Two-hybrid), ACOT8 (Affinity Capture-MS), PML (Affinity Capture-MS), KLHL23 (Affinity Capture-MS), IGHA1 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS), PML (Affinity Capture-MS), KLHL23 (Affinity Capture-MS), IGHA1 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS), ACOT8 (Affinity Capture-MS)

ESM2 similar proteins: A2AIG8, A6NKP2, E9PTA2, O00764, O14734, O15315, O35331, O35719, O43502, O54783, O55229, O94759, P33124, P58137, Q3SWX2, Q3U129, Q4PS77, Q5I0K3, Q5RE34, Q5RJZ1, Q5T1C6, Q5ZM83, Q6AYT9, Q6DC64, Q6GV29, Q6NUN0, Q8BGA8, Q8CIW5, Q8IZ69, Q8K183, Q8K297, Q8N0X4, Q8R2J9, Q8R4N0, Q8TCT0, Q8VCE6, Q8VHK0, Q8VHQ9, Q8WXI4, Q91WC3

Diamond homologs: F4HU51, O14734, O77676, P00516, P0AGG2, P0AGG3, P0C605, P32023, P44498, P58137, P81900, Q03042, Q03043, Q13237, Q13976, Q5FYU1, Q61410, Q64595, Q6C2X0, Q8VHK0, P41903

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ACOT8	“up-regulates quantity”	“coenzyme A(4-)”	“chemical modification”
ACOT8	“down-regulates quantity”	succinyl-CoA(5-)	“chemical modification”
ACOT8	“up-regulates quantity”	glutarate(2-)	“chemical modification”
ACOT8	“down-regulates quantity”	glutaryl-CoA(5-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	43
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2425559	NC_000020.10:g.(?42223339)(44638757_?)del	Pathogenic
3248279	NC_000020.10:g.(?42223339)(45362473_?)del	Pathogenic
813269	Single allele	Likely pathogenic

SpliceAI

926 predictions. Top by Δscore:

Variant	Effect	Δscore
20:45844416:GGTCC:G	acceptor_gain	1.0000
20:45844417:GTCC:G	acceptor_gain	1.0000
20:45844418:TCC:T	acceptor_gain	1.0000
20:45844419:CC:C	acceptor_gain	1.0000
20:45844419:CCC:C	acceptor_gain	1.0000
20:45844420:CC:C	acceptor_gain	1.0000
20:45844421:C:CC	acceptor_gain	1.0000
20:45844422:T:C	acceptor_loss	1.0000
20:45848446:TCA:T	donor_loss	1.0000
20:45848447:CA:C	donor_loss	1.0000
20:45848448:ACCTT:A	donor_loss	1.0000
20:45848449:CCTTA:C	donor_loss	1.0000
20:45855288:TTCCT:T	acceptor_gain	1.0000
20:45855293:C:CC	acceptor_gain	1.0000
20:45844257:TCTTA:T	donor_loss	0.9900
20:45844258:CTTAC:C	donor_loss	0.9900
20:45844260:TAC:T	donor_loss	0.9900
20:45844261:A:AC	donor_gain	0.9900
20:45844261:A:AT	donor_loss	0.9900
20:45844262:C:CC	donor_gain	0.9900
20:45844262:C:CG	donor_loss	0.9900
20:45844421:C:T	acceptor_gain	0.9900
20:45844427:G:C	acceptor_gain	0.9900
20:45844427:G:GC	acceptor_gain	0.9900
20:45848472:T:TA	donor_gain	0.9900
20:45848673:CCC:C	acceptor_gain	0.9900
20:45848674:CC:C	acceptor_gain	0.9900
20:45848674:CCC:C	acceptor_gain	0.9900
20:45848675:CC:C	acceptor_gain	0.9900
20:45848675:CCTGC:C	acceptor_loss	0.9900

AlphaMissense

2080 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:45843673:T:A	D232V	0.998
20:45855169:A:C	F84L	0.997
20:45855169:A:T	F84L	0.997
20:45855171:A:G	F84L	0.997
20:45855256:A:C	F55L	0.997
20:45855256:A:T	F55L	0.997
20:45855258:A:G	F55L	0.997
20:45848554:G:C	F128L	0.996
20:45848554:G:T	F128L	0.996
20:45848556:A:G	F128L	0.996
20:45843537:G:C	S277R	0.995
20:45843537:G:T	S277R	0.995
20:45843539:T:G	S277R	0.995
20:45843672:G:C	D232E	0.995
20:45843672:G:T	D232E	0.995
20:45843673:T:G	D232A	0.995
20:45844287:A:G	W208R	0.995
20:45844287:A:T	W208R	0.995
20:45855175:G:C	C82W	0.995
20:45855224:G:T	A66D	0.995
20:45843590:A:G	W260R	0.994
20:45843590:A:T	W260R	0.994
20:45843685:G:T	A228D	0.994
20:45855177:A:G	C82R	0.994
20:45855239:C:T	G61D	0.994
20:45841886:C:A	Q304H	0.993
20:45841886:C:G	Q304H	0.993
20:45843560:A:G	W270R	0.993
20:45843560:A:T	W270R	0.993
20:45843673:T:C	D232G	0.993

dbSNP variants (sampled 300 via entrez): RS1000110462 (20:45852468 A>G), RS1000294389 (20:45852144 G>A,C), RS1001014183 (20:45847812 TGTTGCCCAGGCTGGA>T), RS1002156649 (20:45858698 T>C), RS1002319046 (20:45842187 C>G,T), RS1002908253 (20:45848522 TG>T), RS1002982046 (20:45845100 T>C), RS1003324229 (20:45843749 C>A,T), RS1003549592 (20:45854339 A>G), RS1003577704 (20:45851331 A>T), RS1003657270 (20:45855855 C>G,T), RS1003808997 (20:45847938 G>A,C), RS1004202513 (20:45847557 G>T), RS1004481575 (20:45851691 A>G,T), RS1004847627 (20:45850429 A>T)

Disease associations

OMIM: gene MIM:608123 | disease phenotypes: MIM:614868, MIM:102700

GenCC curated gene-disease

Mondo (2): combined immunodeficiency due to STK4 deficiency (MONDO:0013934), severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (MONDO:0007064)

Orphanet (2): Combined immunodeficiency due to STK4 deficiency (Orphanet:314689), Severe combined immunodeficiency due to adenosine deaminase deficiency (Orphanet:277)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C531816	Severe combined immunodeficiency due to adenosine deaminase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression	2
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
GW 4064	affects cotreatment, decreases expression	1
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Orlistat	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Amiodarone	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	increases expression, affects cotreatment	1
Smoke	decreases expression	1
Paclitaxel	decreases expression	1
Antirheumatic Agents	decreases expression	1
Oleic Acid	affects cotreatment, decreases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT02022696	PHASE1	COMPLETED	Treatment of SCID Due to ADA Deficiency With Autologous Transplantation of Cord Blood or Hematopoietic CD 34+ Cells After Addition of a Normal Human ADA cDNA by the EFS-ADA Lentiviral Vector
NCT04140539	PHASE2/PHASE3	WITHDRAWN	A Clinical Study to Enable Process Validation of Commercial Grade OTL-101
NCT01279720	PHASE1/PHASE2	COMPLETED	Gene Therapy ADA Deficiency
NCT01380990	PHASE1/PHASE2	COMPLETED	Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
NCT01852071	PHASE1/PHASE2	COMPLETED	Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene
NCT02999984	PHASE1/PHASE2	COMPLETED	Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID
NCT03765632	PHASE1/PHASE2	COMPLETED	Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID
NCT01182857	Not specified	WITHDRAWN	Quality of Life and Neuropsychiatric Sequelae in Patients Treated With Gene Therapy for ADA-SCID and in Their Parents
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT03232203	Not specified	COMPLETED	Evaluating the Effectiveness of STRIMVELIS Risk Minimization Measures (RMMs)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04959890	Not specified	UNKNOWN	Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy
NCT05300334	Not specified	UNKNOWN	Investigation of ADA Enzyme Deficiency
NCT05300347	Not specified	UNKNOWN	Observational Study Evaluating the Prevalence of Enzyme Deficiency in Pulmonology Clinics (ADA)
NCT05300373	Not specified	UNKNOWN	Evaluation of Adenosine Deaminase (ADA) Enzyme Deficiency in Patients With Lymphopenia and/or Elevated Immunoglobulin E