ADH6

Summary

ADH6 (alcohol dehydrogenase 6 (class V), HGNC:255) is a protein-coding gene on chromosome 4q23, encoding Alcohol dehydrogenase 6 (P28332). Alcohol dehydrogenase.

This gene encodes class V alcohol dehydrogenase, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This gene is expressed in the stomach as well as in the liver, and it contains a glucocorticoid response element upstream of its 5’ UTR, which is a steroid hormone receptor binding site. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 130 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 57 total
• Druggable target: yes
• MANE Select transcript: NM_001102470

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:255
Approved symbol	ADH6
Name	alcohol dehydrogenase 6 (class V)
Location	4q23
Locus type	gene with protein product
Status	Approved
Aliases	ADH-5
Ensembl gene	ENSG00000172955
Ensembl biotype	protein_coding
OMIM	103735
Entrez	130

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000237653, ENST00000394897, ENST00000394899, ENST00000504257, ENST00000507484, ENST00000508558, ENST00000512708, ENST00000513262, ENST00000881182, ENST00000881183, ENST00000881184, ENST00000881185, ENST00000881186, ENST00000881187, ENST00000881188, ENST00000881189

RefSeq mRNA: 2 — MANE Select: NM_001102470 NM_000672, NM_001102470

CCDS: CCDS3647, CCDS43255

Canonical transcript exons

ENST00000394899 — 9 exons

Exon	Start	End
ENSE00000801323	99210082	99210298
ENSE00000801325	99213606	99213747
ENSE00001792679	99202639	99204243
ENSE00003484163	99208668	99208928
ENSE00003549321	99216161	99216262
ENSE00003577139	99204925	99205063
ENSE00003636409	99219135	99219246
ENSE00003658238	99210415	99210502
ENSE00003787338	99207446	99207581

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 97.72.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5610 / max 548.0403, expressed in 55 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53259	1.4482	42
53258	0.0372	5
53256	0.0345	6
53253	0.0163	3
53254	0.0122	3
53255	0.0085	4
53257	0.0042	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.72	gold quality
liver	UBERON:0002107	97.53	gold quality
jejunal mucosa	UBERON:0000399	94.85	gold quality
nephron tubule	UBERON:0001231	92.96	gold quality
duodenum	UBERON:0002114	91.91	gold quality
kidney epithelium	UBERON:0004819	90.60	gold quality
pancreatic ductal cell	CL:0002079	88.42	gold quality
right uterine tube	UBERON:0001302	88.10	gold quality
renal glomerulus	UBERON:0000074	87.57	gold quality
metanephric glomerulus	UBERON:0004736	87.38	gold quality
adult mammalian kidney	UBERON:0000082	86.04	gold quality
mucosa of transverse colon	UBERON:0004991	85.73	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.41	gold quality
epithelium of bronchus	UBERON:0002031	85.15	gold quality
bronchial epithelial cell	CL:0002328	85.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.50	gold quality
kidney	UBERON:0002113	83.73	gold quality
bronchus	UBERON:0002185	83.59	gold quality
rectum	UBERON:0001052	82.92	gold quality
ileal mucosa	UBERON:0000331	82.80	gold quality
calcaneal tendon	UBERON:0003701	82.12	gold quality
gall bladder	UBERON:0002110	82.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.61	gold quality
small intestine	UBERON:0002108	79.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	78.73	gold quality
cortex of kidney	UBERON:0001225	78.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.65	gold quality
colonic mucosa	UBERON:0000317	77.96	gold quality
transverse colon	UBERON:0001157	77.40	gold quality
adult organism	UBERON:0007023	77.37	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.49
E-MTAB-9067	no	3.46
E-GEOD-36552	no	1.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, SP1

miRNA regulators (miRDB)

13 targeting ADH6, 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-3924	100.00	72.09	2394
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4275	97.96	68.42	1549

Literature-anchored findings (GeneRIF, showing 3)

• Results show that polymorphism of ADH6 gene leads to heavy drinking in women. (PMID:22690706)
• common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans. (PMID:23468174)
• Local structural differences between human class V ADH and other human ADHs includes a for class V ADH unique and conserved Lys51, a position directly involved in the catalytic mechanism in other ADHs, and nine other class V ADH-specific residues. (PMID:27455956)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	adh8b	ENSDARG00000024278
danio_rerio	adh5l	ENSDARG00000087262
danio_rerio	zgc:77938	ENSDARG00000088366
danio_rerio	adh8a	ENSDARG00000091211
mus_musculus	Adh6b	ENSMUSG00000074206
rattus_norvegicus	Adh1-ps1	ENSRNOG00000065373
rattus_norvegicus	Adh6	ENSRNOG00000069176
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), PTGR3 (ENSG00000180011), ADH1A (ENSG00000187758), ADH7 (ENSG00000196344), ADH1B (ENSG00000196616), ADH5 (ENSG00000197894), ADH4 (ENSG00000198099), CRYZL1 (ENSG00000205758), ADH1C (ENSG00000248144)

Protein

Protein identifiers

Alcohol dehydrogenase 6 — P28332 (reviewed: P28332)

All UniProt accessions (5): P28332, D6RDN5, D6RH17, H0Y8U2, Q8IUN7

UniProt curated annotations — full annotation on UniProt →

Function. Alcohol dehydrogenase. Catalyzes the NAD-dependent oxidation of primary alcohols to the corresponding aldehydes. Oxidizes secondary alcohols to the corresponding ketones.

Subunit / interactions. Dimer.

Subcellular location. Cytoplasm.

Tissue specificity. Stomach and liver.

Activity regulation. Inhibited partially by pyrazole (10 mM) in the reaction mixture containing 100 mM ethanol at pH 10.0.

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. Isoelectric point (pH(I)) is 8.6.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P28332-1	1	yes
P28332-2	2

RefSeq proteins (2): NP_000663, NP_001095940* (*=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

Catalyzed reactions (Rhea), 2 shown:

• a primary alcohol + NAD(+) = an aldehyde + NADH + H(+) (RHEA:10736)
• a secondary alcohol + NAD(+) = a ketone + NADH + H(+) (RHEA:10740)

UniProt features (18 total): binding site 11, sequence variant 3, chain 1, modified residue 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28332-F1	95.87	0.92

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 (11): 47; 229; 293–295; 69; 99; 102; 105; 113; 175; 200–205; 224

Post-translational modifications (1): 23

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-71384	Ethanol oxidation
R-HSA-1430728	Metabolism
R-HSA-211859	Biological oxidations
R-HSA-211945	Phase I - Functionalization of compounds

MSigDB gene sets: 88 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, GNF2_HPN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, KYNG_DNA_DAMAGE_BY_4NQO, CERVERA_SDHB_TARGETS_1_DN, GOBP_RETINOL_METABOLIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, CAIRO_HEPATOBLASTOMA_CLASSES_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GNF2_LCAT, HSIAO_LIVER_SPECIFIC_GENES, GOBP_RETINOIC_ACID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS

GO Biological Process (2): retinol metabolic process (GO:0042572), retinoic acid metabolic process (GO:0042573)

GO Molecular Function (5): alcohol dehydrogenase (NAD+) activity (GO:0004022), all-trans-retinol dehydrogenase (NAD+) activity (GO:0004745), zinc ion binding (GO:0008270), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (3): cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Phase I - Functionalization of compounds	1
Metabolism	1
Biological oxidations	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
retinoid metabolic process	2
hormone metabolic process	2
cellular anatomical structure	2
primary alcohol metabolic process	1
olefinic compound metabolic process	1
monocarboxylic acid metabolic process	1
alcohol dehydrogenase [NAD(P)+] activity	1
alcohol dehydrogenase (NAD+) activity	1
transition metal ion binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADH6	AVP	P01185	946
ADH6	ALDH2	P05091	878
ADH6	ALDH1A1	P00352	703
ADH6	CYP2E1	P05181	608
ADH6	ANKK1	Q8NFD2	602
ADH6	ALDH1B1	P30837	602
ADH6	ALDH3A2	P51648	576
ADH6	ALDH9A1	P49189	572
ADH6	TAS2R16	Q9NYV7	569
ADH6	GABRA6	Q16445	550
ADH6	LDHAL6A	Q6ZMR3	546
ADH6	LDHAL6B	Q9BYZ2	545
ADH6	CHRM2	P08172	538
ADH6	CYP2C9	P11712	524
ADH6	CYP26A1	O43174	522

IntAct

11 interactions, top by confidence:

A	B	Type	Score
ADH6	TNIP1	psi-mi:“MI:0915”(physical association)	0.490
TNIP1	ADH6	psi-mi:“MI:0915”(physical association)	0.490
ADH6	PLEC	psi-mi:“MI:0915”(physical association)	0.400
ADH6	ARRB1	psi-mi:“MI:0915”(physical association)	0.370
ADH6	KRAS	psi-mi:“MI:0915”(physical association)	0.370
RPS29	ADH6	psi-mi:“MI:0915”(physical association)	0.370
ADH6	RSL1D1	psi-mi:“MI:0915”(physical association)	0.370
ADH6	RASSF5	psi-mi:“MI:0915”(physical association)	0.370
RPAIN	ADH6	psi-mi:“MI:0915”(physical association)	0.370
ADH6	ANKRD17	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (11): ADH6 (Proximity Label-MS), PLEC (Proximity Label-MS), ADH6 (Affinity Capture-MS), RASSF5 (Two-hybrid), RSL1D1 (Two-hybrid), ARRB1 (Two-hybrid), KRAS (Two-hybrid), RPS29 (Two-hybrid), TNIP1 (Two-hybrid), ANKRD17 (Two-hybrid), RPAIN (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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1165 predictions. Top by Δscore:

Variant	Effect	Δscore
4:99208663:CAT:C	donor_loss	1.0000
4:99208664:ATA:A	donor_loss	1.0000
4:99208665:TA:T	donor_loss	1.0000
4:99208666:A:AC	donor_gain	1.0000
4:99208666:A:C	donor_loss	1.0000
4:99208667:C:CC	donor_gain	1.0000
4:99208925:TCAC:T	acceptor_gain	1.0000
4:99208926:CACC:C	acceptor_gain	1.0000
4:99208930:T:G	acceptor_loss	1.0000
4:99210408:AACTT:A	donor_loss	1.0000
4:99210409:ACTTA:A	donor_loss	1.0000
4:99210410:CT:C	donor_loss	1.0000
4:99210411:TTA:T	donor_loss	1.0000
4:99210412:TAC:T	donor_loss	1.0000
4:99210413:A:AC	donor_gain	1.0000
4:99210414:C:CC	donor_gain	1.0000
4:99210414:CTTGA:C	donor_gain	1.0000
4:99216174:T:TA	donor_gain	1.0000
4:99208662:ACAT:A	donor_loss	0.9900
4:99208924:GTCAC:G	acceptor_gain	0.9900
4:99208926:CAC:C	acceptor_gain	0.9900
4:99208927:AC:A	acceptor_gain	0.9900
4:99208928:CC:C	acceptor_gain	0.9900
4:99208929:C:CC	acceptor_gain	0.9900
4:99208953:C:CT	acceptor_gain	0.9900
4:99210295:CTGT:C	acceptor_gain	0.9900
4:99210302:T:C	acceptor_gain	0.9900
4:99210304:A:C	acceptor_gain	0.9900
4:99210414:CT:C	donor_gain	0.9900
4:99210414:CTT:C	donor_gain	0.9900

AlphaMissense

2449 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:99216168:C:G	R38P	0.992
4:99210127:G:C	S174R	0.991
4:99210127:G:T	S174R	0.991
4:99210129:T:G	S174R	0.991
4:99213644:A:T	V75D	0.991
4:99208908:A:C	C196W	0.989
4:99210214:G:C	S145R	0.988
4:99210214:G:T	S145R	0.988
4:99210216:T:G	S145R	0.988
4:99208860:A:C	C212W	0.984
4:99208899:A:C	F199L	0.983
4:99208899:A:T	F199L	0.983
4:99208901:A:G	F199L	0.983
4:99208862:A:G	C212R	0.981
4:99216171:A:T	V37D	0.980
4:99210426:A:C	C113W	0.978
4:99207548:C:A	G288W	0.977
4:99207448:C:T	G321E	0.976
4:99207540:A:C	C290W	0.976
4:99210493:A:T	V91D	0.976
4:99216169:G:T	R38S	0.976
4:99208698:G:C	C266W	0.975
4:99208906:G:T	A197D	0.975
4:99207561:G:C	C283W	0.974
4:99208861:C:T	C212Y	0.974
4:99208910:A:G	C196R	0.974
4:99210111:C:A	G180W	0.974
4:99210428:A:G	C113R	0.974
4:99208903:A:T	V198E	0.973
4:99208916:A:G	S194P	0.973

dbSNP variants (sampled 300 via entrez): RS1000086542 (4:99212442 T>G), RS10002894 (4:99220083 G>A,C,T), RS1000518001 (4:99206561 G>A), RS1000690673 (4:99214448 C>G,T), RS10008281 (4:99221145 C>A,T), RS1000882315 (4:99221216 C>T), RS1000897424 (4:99215182 A>G), RS1001168042 (4:99214885 T>A,G), RS1001366362 (4:99220615 A>T), RS1001504107 (4:99207838 C>T), RS1002029452 (4:99206711 T>A), RS1002060755 (4:99207043 T>C), RS1002293420 (4:99215776 C>G,T), RS1002478347 (4:99214512 TA>T), RS10025760 (4:99207390 C>A,T)

Disease associations

OMIM: gene MIM:103735 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000466_2	Esophageal cancer	8.000000e-24
GCST001883_1	Alcohol dependence	3.000000e-21
GCST001920_6	QRS duration	6.000000e-06
GCST006717_3	Alcohol use disorder (dependence and problematic use scores)	8.000000e-13
GCST006718_4	Alcohol use disorder (consumption score)	2.000000e-21
GCST006921_3	Regular attendance at a pub or social club	4.000000e-25
GCST008258_21	Alcohol use disorder (consumption score)	7.000000e-21
GCST90011899_91	Aspartate aminotransferase levels	3.000000e-14
GCST90011900_85	Serum alkaline phosphatase levels	5.000000e-40

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007835	alcohol dependence measurement
EFO:0009592	social interaction measurement
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0009458	alcohol use disorder measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2096668 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	6
Tetrachlorodibenzodioxin	affects cotreatment, affects expression, decreases expression, decreases reaction, affects reaction	6
Cyclosporine	decreases expression, affects cotreatment	5
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
Acetaminophen	decreases expression, affects cotreatment	2
Cadmium	increases abundance, increases expression, decreases expression	2
Valproic Acid	decreases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
bisphenol A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
pentanal	decreases expression	1
nefazodone	decreases expression, affects cotreatment	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
walrycin A	decreases expression	1
Atazanavir Sulfate	affects cotreatment, decreases expression	1
Rosiglitazone	decreases expression	1
Zoledronic Acid	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 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.