ADH4

Summary

ADH4 (alcohol dehydrogenase 4 (class II), pi polypeptide, HGNC:252) is a protein-coding gene on chromosome 4q23, encoding All-trans-retinol dehydrogenase [NAD(+)] ADH4 (P08319). Catalyzes the NAD-dependent oxidation of either all-trans-retinol or 9-cis-retinol.

This gene encodes class II alcohol dehydrogenase 4 pi subunit, which is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class II alcohol dehydrogenase is a homodimer composed of 2 pi subunits. It exhibits a high activity for oxidation of long-chain aliphatic alcohols and aromatic alcohols and is less sensitive to pyrazole. This gene is localized to chromosome 4 in the cluster of alcohol dehydrogenase genes.

Source: NCBI Gene 127 — RefSeq curated summary.

At a glance

• GWAS associations: 27
• Clinical variants (ClinVar): 54 total
• Druggable target: yes
• MANE Select transcript: NM_000670

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:252
Approved symbol	ADH4
Name	alcohol dehydrogenase 4 (class II), pi polypeptide
Location	4q23
Locus type	gene with protein product
Status	Approved
Aliases	ADH-2
Ensembl gene	ENSG00000198099
Ensembl biotype	protein_coding
OMIM	103740
Entrez	127

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265512, ENST00000503416, ENST00000503944, ENST00000504125, ENST00000504581, ENST00000504894, ENST00000505590, ENST00000506705, ENST00000508393, ENST00000509471, ENST00000512499

RefSeq mRNA: 3 — MANE Select: NM_000670 NM_000670, NM_001306171, NM_001306172

CCDS: CCDS34032, CCDS77942

Canonical transcript exons

ENST00000265512 — 9 exons

Exon	Start	End
ENSE00002083855	99123658	99124466
ENSE00003475377	99136466	99136697
ENSE00003489098	99139061	99139148
ENSE00003500400	99127209	99127344
ENSE00003509604	99144205	99144297
ENSE00003560532	99142679	99142780
ENSE00003566072	99131504	99131764
ENSE00003606567	99126594	99126732
ENSE00003621556	99141541	99141682

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 99.29.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.1088 / max 2361.6962, expressed in 62 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53250	3.7587	54
53249	0.2660	16
53247	0.0442	6
53248	0.0223	11
53251	0.0141	3
53252	0.0036	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.29	gold quality
right lobe of liver	UBERON:0001114	99.27	gold quality
liver	UBERON:0002107	98.91	gold quality
duodenum	UBERON:0002114	98.26	gold quality
buccal mucosa cell	CL:0002336	96.32	silver quality
jejunum	UBERON:0002115	95.60	gold quality
sperm	CL:0000019	92.51	gold quality
cerebellar vermis	UBERON:0004720	91.86	silver quality
cardia of stomach	UBERON:0001162	91.79	silver quality
vena cava	UBERON:0004087	91.70	gold quality
tendon of biceps brachii	UBERON:0008188	90.99	silver quality
pylorus	UBERON:0001166	90.83	silver quality
body of tongue	UBERON:0011876	90.47	silver quality
tongue	UBERON:0001723	90.12	silver quality
lateral globus pallidus	UBERON:0002476	89.98	silver quality
superior surface of tongue	UBERON:0007371	89.95	silver quality
ventral tegmental area	UBERON:0002691	89.93	silver quality
subthalamic nucleus	UBERON:0001906	89.86	silver quality
nipple	UBERON:0002030	89.80	silver quality
thymus	UBERON:0002370	89.71	silver quality
trachea	UBERON:0003126	89.70	silver quality
lateral nuclear group of thalamus	UBERON:0002736	89.67	gold quality
pharyngeal mucosa	UBERON:0000355	89.62	silver quality
pericardium	UBERON:0002407	89.59	silver quality
mucosa of stomach	UBERON:0001199	89.50	gold quality
dorsal plus ventral thalamus	UBERON:0001897	89.49	silver quality
inferior vagus X ganglion	UBERON:0005363	89.49	silver quality
substantia nigra pars reticulata	UBERON:0001966	89.46	silver quality
pons	UBERON:0000988	89.31	silver quality
substantia nigra pars compacta	UBERON:0001965	89.15	silver quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	42.61
E-GEOD-36552	no	3.80
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPG, MSC, NR1H4, NRG1, TBP

miRNA regulators (miRDB)

44 targeting ADH4, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-1911-3P	99.15	66.17	528
HSA-MIR-4796-3P	99.08	68.38	1681

Literature-anchored findings (GeneRIF, showing 29)

• Thirteen new single nucleotide polymorphisms (PMID:11916005)
• Identification and characterisation of two allelic forms of human alcohol dehydrogenase 2 (PMID:11964133)
• kinetic mechanisms for ADH4 functioning as retinol dehydrogenase (PMID:11997393)
• Results describe the expression patterns of alcohol dehydrogenases I, III, and IV in adult rat, mouse and human tissues using radioactive oligonucleotide in situ hybridization. (PMID:12631290)
• The mean alcohol-elimination rate among ADH2*2 carriers is significantly higher than among ADH2*1 homozygotes in a male Jewish population. (PMID:14745297)
• the genotypes of six ADH4 markers were associated with alcohol dependence, and all seven ADH4 markers were associated with drug dependence (PMID:16220108)
• Seven single nucleotide polymorphisms spanning the ADH4 gene were genotyped in 561 subjects affected with alcohol dependence and/or drug dependence. (PMID:16237392)
• that personality traits and substance dependence have a partially overlapping genetic basis. (PMID:17069770)
• Class II alcohol dehydogenase (ADH4) is considered to contribute to ethanol oxidation in the liver at high concentration. (PMID:19182438)
• ADH4 gene polymorphisms are associated with upper aerodigestive tract cancers. (PMID:19861527)
• Our data suggest that cluster headache is associated with the ADH4 gene or a linked locus. Additional studies are warranted to elucidate the role of this gene in the etiopathogenesis of the disease. (PMID:19925625)
• In this study we have identified a distal upstream enhancer, 4E, of ADH4. In HepG2 human hepatoma cells, 4E increased the activity of an ADH4 basal promoter by 50-fold. 4E was cell-specific. (PMID:20363298)
• This study confirms the significant relationship of ADH4 variants with AD and related phenotypes. (PMID:20626721)
• the high catalytic activity of human alcohol dehydrogenase 4 studied with horse liver ADH1E (PMID:21184752)
• Data indicate that further studies of EPHX1 rs1051740, ADH4 r1042364, and NQO1 rs291766 are needed to make more definitive conclusion on the role of variation in xenobiotic metabolism in ovarian cancer. (PMID:21480392)
• Variants in the ADH1B and ADH4 genes may be protective against the development of some symptoms associated with alcohol dependence. (PMID:21635275)
• data suggest that ADH4 intronic variants play a role in alcohol dependence susceptibility in Italian populations (PMID:22044940)
• expression levels of ADH4 mRNA and protein have found to be markedly reduced in hepatocellular carcinoma (HCC) tissues and significantly associated with survival. (PMID:22147505)
• Our results suggest that the analysed polymorphisms ofANKK1 and ADH4 can play an important part in the pathogenesis of alcohol abuse (PMID:22232963)
• common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans. (PMID:23468174)
• The serum expression of ADH4 protein correlates with the progression of esophageal cancer. (PMID:24051444)
• This study confirmed the genetic heterogeneity of cluster headache, suggesting that mutations in the ADH4 gene might be related to cluster headache in a subset of cases. (PMID:24469609)
• this current study provides substantial evidence that genetic polymorphisms of rs3805322 in the ADH4 gene may be associated with an increased risk of developing ESCC in two Chinese Han populations. (PMID:26039424)
• Association between HCRTR2, ADH4,CLOCK gene polymorphisms and cluster headache was not significant in the present study. (PMID:29318394)
• ADH4 expression is significantly downregulated in healthy palatal mucosa of smokers (PMID:31682009)
• Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population. (PMID:31768945)
• A novel mechanism underlying alcohol dehydrogenase expression: hsa-miR-148a-3p promotes ADH4 expression via an AGO1-dependent manner in control and ethanol-exposed hepatic cells. (PMID:33556337)
• No significant association between SNPs in the CLOCK and ADH4 genes and susceptibility to cluster headaches: A systematic review and meta-analysis. (PMID:35437765)
• Novel Insights into MEG3/miR664a-3p/ADH4 Axis and Its Possible Role in Hepatocellular Carcinoma from an in Silico Perspective. (PMID:36553522)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	adh8b	ENSDARG00000024278
danio_rerio	adh5l	ENSDARG00000087262
danio_rerio	zgc:77938	ENSDARG00000088366
danio_rerio	adh8a	ENSDARG00000091211
mus_musculus	Adh4	ENSMUSG00000037797
rattus_norvegicus	Adh4	ENSRNOG00000046357
drosophila_melanogaster	Drat	FBGN0033188
caenorhabditis_elegans		WBGENE00010790
caenorhabditis_elegans		WBGENE00010791
caenorhabditis_elegans		WBGENE00014096
caenorhabditis_elegans		WBGENE00017060

Paralogs (17): PTGR1 (ENSG00000106853), VAT1 (ENSG00000108828), TP53I3 (ENSG00000115129), MECR (ENSG00000116353), CRYZ (ENSG00000116791), RTN4IP1 (ENSG00000130347), PTGR2 (ENSG00000140043), SORD (ENSG00000140263), VAT1L (ENSG00000171724), ADH6 (ENSG00000172955), PTGR3 (ENSG00000180011), ADH1A (ENSG00000187758), ADH7 (ENSG00000196344), ADH1B (ENSG00000196616), ADH5 (ENSG00000197894), CRYZL1 (ENSG00000205758), ADH1C (ENSG00000248144)

Protein

Protein identifiers

All-trans-retinol dehydrogenase [NAD(+)] ADH4 — P08319 (reviewed: P08319)

Alternative names: Alcohol dehydrogenase 2, Alcohol dehydrogenase 4, Alcohol dehydrogenase class II pi chain

All UniProt accessions (5): P08319, D6R9K8, D6RF43, D6RIB1, H0Y9N0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the NAD-dependent oxidation of either all-trans-retinol or 9-cis-retinol. Also oxidizes long chain omega-hydroxy fatty acids, such as 20-HETE, producing both the intermediate aldehyde, 20-oxoarachidonate and the end product, a dicarboxylic acid, (5Z,8Z,11Z,14Z)-eicosatetraenedioate. Also catalyzes the reduction of benzoquinones.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Activity regulation. Oxydation of 20-HETE is inhibited by low concentrations of N-heptylformamide. Oxydation of 20-HETE is a decreased by 55-65% by either all-trans-retinol or all-trans-retinoic acid. Strongly inhibited by omega-hydroxy fatty acids.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Miscellaneous. There are 7 different ADH’s isozymes in human: three belongs to class-I: alpha, beta, and gamma, one to class-II: pi, one to class-III: chi, one to class-IV: ADH7 and one to class-V: ADH6.

Similarity. Belongs to the zinc-containing alcohol dehydrogenase family. Class-II subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P08319-1	1	yes
P08319-2	2

RefSeq proteins (3): NP_000661, NP_001293100, NP_001293101 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002328	ADH_Zn_CS	Conserved_site
IPR011032	GroES-like_sf	Homologous_superfamily
IPR013149	ADH-like_C	Domain
IPR013154	ADH-like_N	Domain
IPR020843	ER	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00107, PF08240

Enzyme classification (BRENDA):

• EC 1.1.1.1 — alcohol dehydrogenase (BRENDA: 143 organisms, 1348 substrates, 378 inhibitors, 1051 Km, 600 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ETHANOL	0.0172–5000	148
NAD+	0.001–710	111
NADH	0.0004–260	62
ACETALDEHYDE	0.0086–121	51
BENZYL ALCOHOL	0.007–49	38
CYCLOHEXANOL	0.008–1900	21
2,3-BUTANEDIOL	0.44–1100	19
BENZALDEHYDE	0.03–33	13
NADP+	0.0051–360	13
12-HYDROXYDODECANOATE	0.013–2.3	12
2-PROPANOL	0.6–560	12
1-PROPANOL	0.24–39.8	11
4-METHOXYBENZYL ALCOHOL	0.07–61	10
ALL-TRANS-RETINOL	0.009–0.059	10
BUTANOL	0.012–53.9	10

Catalyzed reactions (Rhea), 5 shown:

• all-trans-retinol + NAD(+) = all-trans-retinal + NADH + H(+) (RHEA:21284)
• 20-hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate + NAD(+) = 20-oxo-(5Z,8Z,11Z,14Z)-eicosatetraenoate + NADH + H(+) (RHEA:39799)
• 20-oxo-(5Z,8Z,11Z,14Z)-eicosatetraenoate + NAD(+) + H2O = (5Z,8Z,11Z,14Z)-eicosatetraenedioate + NADH + 2 H(+) (RHEA:39803)
• 9-cis-retinol + NAD(+) = 9-cis-retinal + NADH + H(+) (RHEA:42052)
• 1,4-benzoquinone + NADH + H(+) = hydroquinone + NAD(+) (RHEA:60660)

UniProt features (64 total): strand 20, helix 17, binding site 14, turn 4, sequence variant 3, modified residue 2, sequence conflict 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3COS	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08319-F1	98.23	0.99

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 (14): 47; 229; 234; 298–300; 323–325; 375; 48–49; 69; 99; 102; 105; 113 …

Post-translational modifications (2): 121, 278

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5365859	RA biosynthesis pathway
R-HSA-71384	Ethanol oxidation
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-211859	Biological oxidations
R-HSA-211945	Phase I - Functionalization of compounds
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-9006931	Signaling by Nuclear Receptors

MSigDB gene sets: 159 (showing top): GOBP_LIPID_MODIFICATION, MODULE_93, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_ALDEHYDE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_KETONE_METABOLIC_PROCESS, UEDA_PERIFERAL_CLOCK, MODULE_272, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (10): retinoid metabolic process (GO:0001523), alcohol metabolic process (GO:0006066), ethanol metabolic process (GO:0006067), aldehyde metabolic process (GO:0006081), fatty acid omega-oxidation (GO:0010430), retinol metabolic process (GO:0042572), alcohol catabolic process (GO:0046164), formaldehyde catabolic process (GO:0046294), quinone metabolic process (GO:1901661), lipid metabolic process (GO:0006629)

GO Molecular Function (13): quinone reductase (NADPH) activity (GO:0003960), alcohol dehydrogenase (NAD+) activity (GO:0004022), aldose reductase (NADPH) activity (GO:0004032), all-trans-retinol dehydrogenase (NAD+) activity (GO:0004745), all-trans retinal binding (GO:0005503), zinc ion binding (GO:0008270), benzaldehyde dehydrogenase (NAD+) activity (GO:0018479), retinol binding (GO:0019841), NAD binding (GO:0051287), S-(hydroxymethyl)glutathione dehydrogenase [NAD(P)+] activity (GO:0051903), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleoplasm (GO:0005654), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by Retinoic Acid	1
Phase I - Functionalization of compounds	1
Metabolism	1
Biological oxidations	1
Signaling by Nuclear Receptors	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
primary alcohol metabolic process	2
small molecule catabolic process	2
diterpenoid metabolic process	1
small molecule metabolic process	1
metabolic process	1
fatty acid oxidation	1
retinoid metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
alcohol metabolic process	1
aldehyde catabolic process	1
formaldehyde metabolic process	1
cellular detoxification of aldehyde	1
ketone metabolic process	1
primary metabolic process	1
NADPH dehydrogenase activity	1
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	1
alcohol dehydrogenase [NAD(P)+] activity	1
alcohol dehydrogenase (NADP+) activity	1
alcohol dehydrogenase (NAD+) activity	1
retinal binding	1
transition metal ion binding	1
aldehyde dehydrogenase (NAD+) activity	1
retinoid binding	1
vitamin binding	1
alcohol binding	1
adenyl nucleotide binding	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADH4	AVP	P01185	947
ADH4	ALDH2	P05091	926
ADH4	ALDH1A1	P00352	822
ADH4	ALDH3A2	P51648	616
ADH4	CYP2E1	P05181	600
ADH4	ALDH3B1	P43353	560
ADH4	ALDH3A1	P30838	553
ADH4	ALDH1B1	P30837	539
ADH4	GSTM1	P09488	531
ADH4	SPANXN3	Q5MJ09	526
ADH4	LDHAL6B	Q9BYZ2	516
ADH4	LDHAL6A	Q6ZMR3	515
ADH4	GABRA2	P47869	505
ADH4	ALDH9A1	P49189	484
ADH4	CYP2B6	P20813	473

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TRIM69	ADH4	psi-mi:“MI:0915”(physical association)	0.560
ADH4	TRIM69	psi-mi:“MI:0915”(physical association)	0.560
ADH4	RPL35	psi-mi:“MI:0915”(physical association)	0.370
	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): ADH4 (Affinity Capture-MS), ADH4 (Affinity Capture-MS), APP (Reconstituted Complex), ADH4 (Affinity Capture-MS), RPL35 (Two-hybrid)

ESM2 similar proteins: A0A0C5DM37, A0A0U3S9Q3, A0A0U4BHM2, A0A161CAI1, A0A1B1FHP3, A0A2I7G3B2, A0A2I7G3B3, A0A2U1Q018, A0A9E7LUR3, A1L4Y2, B2NI93, E5AE42, O46649, O46650, O57380, O64969, O74540, O94564, P08319, P0CL53, P0DO83, P0DXF9, P0DXJ1, P22797, P25377, P26325, P28332, P30359, P30360, P39714, P40394, P41681, P41682, P48523, P78870, P80468, P86883, Q32L99, Q42726, Q5R7Z8

Diamond homologs: A0A0C5DM37, A0A2I7G3B2, A0A2I7G3B3, A0A2U1Q018, A1A835, A1L4Y2, A2XAZ3, A7ZIA4, A7ZX04, B1J085, B1LIP1, O19053, O74540, O97959, P00325, P00326, P00327, P00328, P00329, P00333, P04707, P05336, P06525, P06757, P07327, P08319, P0CL53, P10847, P10848, P11766, P12711, P12886, P13603, P14139, P14219, P14673, P14674, P14675, P17648, P19631

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1133 predictions. Top by Δscore:

Variant	Effect	Δscore
4:99142674:CTTA:C	donor_loss	1.0000
4:99142675:TTAC:T	donor_loss	1.0000
4:99142676:TAC:T	donor_loss	1.0000
4:99142677:A:AC	donor_gain	1.0000
4:99142677:A:AT	donor_loss	1.0000
4:99142677:AC:A	donor_gain	1.0000
4:99142678:C:CA	donor_gain	1.0000
4:99142678:CC:C	donor_gain	1.0000
4:99142678:CCT:C	donor_gain	1.0000
4:99142678:CCTG:C	donor_gain	1.0000
4:99142678:CCTGA:C	donor_gain	1.0000
4:99142777:TAAC:T	acceptor_gain	1.0000
4:99142779:AC:A	acceptor_gain	1.0000
4:99142780:CC:C	acceptor_gain	1.0000
4:99142781:C:CC	acceptor_gain	1.0000
4:99144195:A:AC	donor_gain	1.0000
4:99144196:C:CC	donor_gain	1.0000
4:99144196:CTTG:C	donor_gain	1.0000
4:99144203:A:AC	donor_gain	1.0000
4:99144204:C:CC	donor_gain	1.0000
4:99124465:CG:C	acceptor_gain	0.9900
4:99124467:C:CC	acceptor_gain	0.9900
4:99126589:TGTA:T	donor_loss	0.9900
4:99126590:GTAC:G	donor_loss	0.9900
4:99126591:TACC:T	donor_loss	0.9900
4:99126592:ACCT:A	donor_loss	0.9900
4:99126593:C:T	donor_loss	0.9900
4:99126626:A:AC	donor_gain	0.9900
4:99126627:C:CC	donor_gain	0.9900
4:99126730:AACC:A	acceptor_loss	0.9900

AlphaMissense

2493 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:99136598:A:C	S150R	0.993
4:99136598:A:T	S150R	0.993
4:99136600:T:G	S150R	0.993
4:99142686:C:G	R38P	0.990
4:99136599:C:A	S150I	0.989
4:99141664:A:G	C47R	0.988
4:99131742:G:T	A202D	0.987
4:99131698:A:G	C217R	0.986
4:99141594:T:A	E70V	0.986
4:99141600:C:A	G68V	0.986
4:99131739:A:T	V203D	0.985
4:99136494:C:T	G185D	0.985
4:99127211:C:T	G326D	0.984
4:99131525:A:C	C274W	0.984
4:99139096:A:C	C105W	0.984
4:99131744:A:C	C201W	0.983
4:99136641:A:G	F136S	0.983
4:99141596:A:C	H69Q	0.983
4:99141596:A:T	H69Q	0.983
4:99141662:G:C	C47W	0.983
4:99131710:C:G	A213P	0.982
4:99131718:C:T	G210D	0.982
4:99127211:C:A	G326V	0.981
4:99131700:C:T	G216D	0.981
4:99141579:A:T	V75E	0.981
4:99141600:C:T	G68D	0.981
4:99141655:C:G	D50H	0.981
4:99136510:A:G	C180R	0.980
4:99141597:T:G	H69P	0.980
4:99141598:G:C	H69D	0.979

dbSNP variants (sampled 300 via entrez): RS1000224044 (4:99131679 G>A), RS1000444510 (4:99128812 T>TC), RS1000451530 (4:99137878 A>G), RS1000454489 (4:99142620 G>C), RS1000467131 (4:99145323 G>A), RS1000781493 (4:99125383 G>A,T), RS1000818053 (4:99144942 A>G), RS10009145 (4:99126778 G>A), RS1000947343 (4:99123594 T>A), RS1001176278 (4:99130443 G>C), RS10014222 (4:99140913 A>C,G,T), RS1001696187 (4:99145909 G>A), RS1001709713 (4:99138537 T>C), RS10017466 (4:99134649 C>A,G,T), RS1001793065 (4:99143739 G>A,C)

Disease associations

OMIM: gene MIM:103740 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST001672_2	Esophageal cancer (alcohol interaction)	6.000000e-07
GCST001883_1	Alcohol dependence	3.000000e-21
GCST002388_13	Serum metabolite levels	2.000000e-15
GCST004711_19	Alcohol dependence	1.000000e-06
GCST004711_21	Alcohol dependence	2.000000e-06
GCST004711_22	Alcohol dependence	2.000000e-06
GCST004711_23	Alcohol dependence	9.000000e-06
GCST004711_31	Alcohol dependence	2.000000e-06
GCST004711_32	Alcohol dependence	3.000000e-06
GCST004711_33	Alcohol dependence	3.000000e-06
GCST004711_35	Alcohol dependence	5.000000e-06
GCST004711_41	Alcohol dependence	6.000000e-06
GCST004711_46	Alcohol dependence	7.000000e-06
GCST004712_19	Alcohol dependence	3.000000e-06
GCST006585_1706	Blood protein levels	4.000000e-10
GCST006921_3	Regular attendance at a pub or social club	4.000000e-25
GCST007401_36	Factor VII activity	1.000000e-12
GCST007401_4	Factor VII activity	3.000000e-13
GCST007402_5	Factor VII activity or levels	4.000000e-11
GCST008259_23	Alcohol use disorder	1.000000e-09
GCST010241_207	Apolipoprotein A1 levels	1.000000e-09
GCST010244_385	Triglyceride levels	1.000000e-10
GCST011353_38	Serum alkaline phosphatase levels	5.000000e-08
GCST011955_6	Alcohol dependence	7.000000e-06
GCST90011899_91	Aspartate aminotransferase levels	3.000000e-14
GCST90011900_85	Serum alkaline phosphatase levels	5.000000e-40
GCST90013406_20	Liver enzyme levels (alkaline phosphatase)	9.000000e-86

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007835	alcohol dependence measurement
EFO:0009592	social interaction measurement
EFO:0004619	factor VII measurement
EFO:0009458	alcohol use disorder measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004530	triglyceride measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096668 (PROTEIN FAMILY), CHEMBL2990 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.15	Ki	7100	nM	CHEMBL291214

PubChem BioAssay actives

1 with measured affinity, of 57 total; 1 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
N-(cyclohexylmethyl)formamide	34042: Inhibition of human alcohol dehydrogenase pi activity	ki	7.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects reaction, affects cotreatment, increases reaction, decreases expression, decreases reaction	7
Ethanol	decreases reaction, increases metabolic processing, affects oxidation, increases oxidation	4
Cyclosporine	decreases expression, affects cotreatment	4
perfluorooctane sulfonic acid	decreases expression, affects cotreatment	3
Acetaminophen	affects cotreatment, decreases expression	3
Aflatoxin B1	decreases expression, decreases methylation, affects expression	3
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	2
perfluorooctanoic acid	affects cotreatment, decreases expression	2
perfluoro-n-nonanoic acid	decreases expression, affects cotreatment	2
Rosiglitazone	decreases expression	2
Benzo(a)pyrene	decreases expression	2
Chenodeoxycholic Acid	decreases expression, affects cotreatment	2
Deoxycholic Acid	decreases expression, affects cotreatment	2
Endosulfan	affects cotreatment, decreases expression, increases reaction	2
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	2
Glycocholic Acid	affects cotreatment, decreases expression	2
Glycodeoxycholic Acid	affects cotreatment, decreases expression	2
Phenobarbital	decreases expression, increases expression	2
Tartrazine	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression	2
dicrotophos	decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects expression	1
2,6-dichloro-4-nitrophenol	decreases reaction, increases metabolic processing	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
butylbenzyl phthalate	decreases expression	1
nefazodone	affects cotreatment, decreases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3257323	Binding	Inhibition of alcohol dehydrogenase (unknown origin) assessed as dissociation constant for the complex of enzyme and DPNH	A manual method for applying the Hansch approach to drug design. — J Med Chem

Clinical trials (associated diseases)

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