ADH1C

Summary

ADH1C (alcohol dehydrogenase 1C (class I), gamma polypeptide, HGNC:251) is a protein-coding gene on chromosome 4q23, encoding Alcohol dehydrogenase 1C (P00326). Alcohol dehydrogenase.

This gene encodes class I alcohol dehydrogenase, gamma 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 I alcohol dehydrogenase, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation to acetaldehyde, thus playing a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. An association between ADH1C polymorphism and alcohol dependence has not been established.

Source: NCBI Gene 126 — RefSeq curated summary.

At a glance

• GWAS associations: 47
• Clinical variants (ClinVar): 63 total
• Phenotypes (HPO): 32
• Druggable target: yes
• MANE Select transcript: NM_000669

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:251
Approved symbol	ADH1C
Name	alcohol dehydrogenase 1C (class I), gamma polypeptide
Location	4q23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000248144
Ensembl biotype	protein_coding
OMIM	103730
Entrez	126

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000505942, ENST00000510055, ENST00000511397, ENST00000515683, ENST00000865215, ENST00000865216, ENST00000865217, ENST00000865218, ENST00000865219, ENST00000865220, ENST00000865221, ENST00000865222, ENST00000865223, ENST00000865224

RefSeq mRNA: 1 — MANE Select: NM_000669 NM_000669

CCDS: CCDS54780

Canonical transcript exons

ENST00000515683 — 9 exons

Exon	Start	End
ENSE00002020292	99352658	99352746
ENSE00002033151	99336497	99336776
ENSE00002490539	99339577	99339715
ENSE00002498661	99340575	99340710
ENSE00002526688	99342795	99343055
ENSE00003646872	99347745	99347846
ENSE00003719115	99344862	99345081
ENSE00003727929	99345179	99345266
ENSE00003755310	99347006	99347144

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 99.12.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.8397 / max 3277.2853, expressed in 152 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53272	4.8397	152

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.12	gold quality
jejunal mucosa	UBERON:0000399	99.08	gold quality
nasal cavity epithelium	UBERON:0005384	98.93	gold quality
right lobe of liver	UBERON:0001114	98.79	gold quality
colonic mucosa	UBERON:0000317	98.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.74	gold quality
duodenum	UBERON:0002114	98.70	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.58	gold quality
rectum	UBERON:0001052	98.21	gold quality
palpebral conjunctiva	UBERON:0001812	97.76	gold quality
bronchial epithelial cell	CL:0002328	97.66	gold quality
liver	UBERON:0002107	97.40	gold quality
epithelium of bronchus	UBERON:0002031	97.38	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.13	gold quality
bronchus	UBERON:0002185	96.82	gold quality
nasal cavity mucosa	UBERON:0001826	96.81	gold quality
pylorus	UBERON:0001166	96.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.13	gold quality
gall bladder	UBERON:0002110	94.80	gold quality
transverse colon	UBERON:0001157	94.32	gold quality
colonic epithelium	UBERON:0000397	94.00	gold quality
parietal pleura	UBERON:0002400	91.83	gold quality
jejunum	UBERON:0002115	91.77	gold quality
body of stomach	UBERON:0001161	91.66	gold quality
ileal mucosa	UBERON:0000331	91.52	gold quality
small intestine	UBERON:0002108	91.29	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.24	gold quality
stomach	UBERON:0000945	90.63	gold quality
tibial nerve	UBERON:0001323	90.51	gold quality
intestine	UBERON:0000160	89.51	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	617.99
E-MTAB-10553	yes	38.42
E-HCAD-10	yes	20.87
E-HCAD-31	no	3.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPG, DBP, DDIT3, DNMT1, GATA2, RARB, SREBF1, TBP, USF1

miRNA regulators (miRDB)

18 targeting ADH1C, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-135A-2-3P	98.40	66.74	442
HSA-MIR-135B-3P	98.40	67.35	426
HSA-MIR-4468	98.01	66.85	1187
HSA-MIR-2278	97.30	66.19	1130
HSA-MIR-4790-3P	96.63	67.08	806
HSA-MIR-662	90.64	62.72	148

Literature-anchored findings (GeneRIF, showing 40)

• A new coding variant has been identified at codon 351 of ADH1C, an allele found in most Native American populations studied, with allele frequencies of the new ADH1C*351Thr allele as high as 26%. (PMID:12500098)
• Polymorphisms of alcohol-metabolizing enzymes: analyses of mutations on the CYP2E1, ADH2, ADH3 and ALDH2 genes in a Mexican-American population living in the Los Angeles area. (PMID:12554615)
• Results suggest that alcohol dehydrogenase 3 catalysed S-nitrosoglutathione reduction is of physiological relevance in the metabolism of NO in humans. (PMID:12631283)
• There is no significant interaction between alcohol consumption and ADH3 genotype. (PMID:12658118)
• Polymorphism is not associated with laryngeal cancer risk in Caucasians. (PMID:12668919)
• adh3 gene is implicated in alcoholism incidence among African Americans (PMID:12713190)
• gastric ADH3 may highly effectively contribute to the first-pass metabolism at 0.5-3 M ethanol, an attainable range in the gastric lumen during alcohol consumption (PMID:12782305)
• mutations in genes encoding ADH1C (G78Stop) as genetic risk factors for Parkinson disease . (PMID:15642852)
• ADH1C polymorphisms in the cis-acting elements affect transcription. (PMID:15643610)
• a slower alcohol clearance rate is associated with the ADH3 y2 allele [letter] (PMID:15842377)
• mean corpuscular volume values were not associated with genotype polymorphisms of ADH1C (PMID:15897724)
• No association has been revealed for the alcohol metabolism-related ADH3 genotype and Korean patients with alcoholism compared to Korean control subjects without alcoholism. (PMID:15902904)
• Conversely, in both genders, no differences were found between ADH3 genotypes regarding all cardiovascular risk factors studied and carotid intima-media thickness. (PMID:15941567)
• ADH1C genotype modifies the association between alcohol consumption and HDL levels among men and postmenopausal women not using postmenopausal hormones who drink moderately (PMID:16051248)
• polymorphisms in ADH1C and ADH1B may have roles in the risk of alcoholism (PMID:16086315)
• Alcohol dehydrogenase 3 null genotypes did not modify the risk of HCC due to alcohol intake. (PMID:16132793)
• No effects of the ADH1C*349Ile alleles on in vivo ethanol metabolism were observed. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by this polymorphism. (PMID:16184481)
• HNF1 binding, at approximately 51 kb upstream, plays a master role in controlling human class I alcohol dehydrogenase gene expression. (PMID:16675441)
• findings suggest that the alcohol dehydrogenase IB and IC genes are regulated by epigenetic mechanisms in human hepatoma cells (PMID:16737450)
• There were no differences in the frequencies of genotypes of ADH2 and ADH3 between trichloroethylene-induced medicamentosa-like dermatitis cases and exposed controls. (PMID:16758956)
• Genetic polymorphisms of ADH1C is associated with oral and pharyngeal squamous cell carcinoma (PMID:17071628)
• These results suggest that ADH1C polymorphisms are associated with alcohol dependence and alcohol associated elevations of liver enzymes in a population with a low frequency of ADH1B2 alleles. (PMID:17134660)
• Polymorphisms in ADH1C is associated with breast cancer (PMID:17268812)
• Low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1C gene. (PMID:17295732)
• Our findings do not support the hypothesis that ADH1C variants are associated with coronary heart disease risk in people who drink moderately. (PMID:17379229)
• The researchers found evidence for a functional allele polymorphic with a strong specific linkage disequilibrium in an Indian population, and this is an important factor in the metabolism of ethanol to acetaldehyde. (PMID:17421009)
• The ADH1C*1 allele frequency and rate of homozygosity was significantly associated with an increased risk for alcohol-related cancer. (PMID:17543846)
• examined genetic polymorphisms in the alcohol dehydrogenase 3, aldehyde dehydrogenase 2, and cytochrome P450 2E1 genes in 505 patients with histologically confirmed lung cancer and 256 noncancer controls to determine association with alcohol drinking (PMID:17559142)
• ADH1C*2 allele, related to slower oxidation rate, attenuates the lower diabetes risk among moderate to heavy drinkers. (PMID:17563066)
• Data suggest that ADH3 genotype may be associated with risk of esophageal and stomach cardia adenocarcionoma. (PMID:17665311)
• individuals with ADH1C slow vs fast alcohol degradation had a higher risk of heavy and excessive drinking. (PMID:17923853)
• Alcohol dehydrogenase modifies the effect of alcohol consumption on coronary risk. The results support the protective effect of alcohol consumption on CHD risk and suggest a causal association of alcohol intake and lower CHD risk. (PMID:18043297)
• It was observed that ADH variants, ADH2*1 and ADH3*2, were associated with increased risk for oesophageal cancer, possibly due to the tolerance of the carriers of these alleles to alcohol consumption (PMID:18254707)
• study suggests the association of ADH1C*2/*2/MTHFR 677TT genotype combination as a risk factor for oral squamous cell carcinoma in alcoholics (PMID:18266839)
• Polymorphisms in ADH1C may not be associated with risk of colorectal adenoma, but may interact with nutrients in the one-carbon pathway to affect adenoma risk. (PMID:18268116)
• Reduction of S-nitrosoglutathione by alcohol dehydrogenase 3 is facilitated by substrate alcohols via direct cofactor recycling and leads to GSH-controlled formation of glutathione transferase inhibitors (PMID:19038239)
• Polymorphisms in ADH1C is associated with pancreatic cancer. (PMID:19068087)
• ADH1C homozygosity is a genetic risk marker for colorectal tumors in individuals consuming more than 30 g alcohol per day. (PMID:19120062)
• Results suggest a slightly increased risk of larynx cancer for indeividuals who have inherited the ADH1C*1 allele, however results were not at statistic significance level. (PMID:19189524)
• Report associations between genetic variation of alcohol dehydrogenase type 1C (ADH1C), alcohol consumption, and metabolic cardiovascular risk factors. (PMID:19447389)

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	Adh1	ENSMUSG00000074207
rattus_norvegicus	Adh1c	ENSRNOG00000012436
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), ADH4 (ENSG00000198099), CRYZL1 (ENSG00000205758)

Protein

Protein identifiers

Alcohol dehydrogenase 1C — P00326 (reviewed: P00326)

Alternative names: Alcohol dehydrogenase subunit gamma

All UniProt accessions (3): A0A087WU81, A0A087WUC4, P00326

UniProt curated annotations — full annotation on UniProt →

Function. Alcohol dehydrogenase. Exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism.

Subunit / interactions. Dimer of identical or non-identical chains of class I alcohol dehydrogenase: ADH1A, ADH1B, and ADH1C.

Subcellular location. Cytoplasm.

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

Polymorphism. Two main alleles are known, ADH31 or gamma-1 has Arg-272/Ile-350 while ADH32 or gamma-2 has Gln-272/Val-350. ADH31 is associated with a fast rate of ethanol oxidation and ADH32 with a slow rate.

Miscellaneous. There are 7 different ADH’s isozymes in human: three belongs to class-I: ADH1A, ADH1B, and ADH1C, one to class-II: ADH4, one to class-III: ADH5, one to class-IV: ADH7 and one to class-V: ADH6.

Similarity. Belongs to the zinc-containing alcohol dehydrogenase family.

RefSeq proteins (1): NP_000660* (*=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), 2 shown:

• a primary alcohol + NAD(+) = an aldehyde + NADH + H(+) (RHEA:10736)
• ethanol + NAD(+) = acetaldehyde + NADH + H(+) (RHEA:25290)

UniProt features (68 total): strand 21, helix 18, binding site 14, sequence variant 5, turn 4, modified residue 2, sequence conflict 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1U3W	X-RAY DIFFRACTION	1.45
1HT0	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00326-F1	98.13	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): 224; 229; 270; 293–295; 318–320; 370; 47; 68; 98; 101; 104; 112 …

Post-translational modifications (2): 2, 23

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: 235 (showing top): MODULE_93, REACTOME_BIOLOGICAL_OXIDATIONS, GNF2_GSTM1, GNF2_HPN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, CAIRO_HEPATOBLASTOMA_CLASSES_DN, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GNF2_LCAT, BROWNE_HCMV_INFECTION_14HR_DN, CAIRO_HEPATOBLASTOMA_DN, GOBP_RETINOIC_ACID_METABOLIC_PROCESS

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

GO Molecular Function (7): alcohol dehydrogenase (NAD+) activity (GO:0004022), all-trans-retinol dehydrogenase (NAD+) activity (GO:0004745), zinc ion binding (GO:0008270), ethanol dehydrogenase (NAD+) activity (GO:0120542), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), 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	4
retinoid metabolic process	2
hormone metabolic process	2
alcohol dehydrogenase (NAD+) activity	2
cilium	2
primary alcohol metabolic process	1
olefinic compound metabolic process	1
monocarboxylic acid metabolic process	1
alcohol dehydrogenase [NAD(P)+] activity	1
transition metal ion binding	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
microtubule organizing center	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADH1C	ALDH2	P05091	959
ADH1C	AVP	P01185	956
ADH1C	ALDH1A1	P00352	687
ADH1C	CYP2E1	P05181	637
ADH1C	ALDH1B1	P30837	605
ADH1C	ANKK1	Q8NFD2	590
ADH1C	MANBA	O00462	549
ADH1C	EPHX1	P07099	548
ADH1C	CHRM2	P08172	541
ADH1C	GIGYF2	Q6Y7W6	518
ADH1C	ALDH3A2	P51648	502
ADH1C	CYP3A5	P20815	492
ADH1C	FBXO7	Q9Y3I1	490
ADH1C	LDHAL6A	Q6ZMR3	490
ADH1C	LDHAL6B	Q9BYZ2	490

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ADH1C	ADH1B	psi-mi:“MI:0914”(association)	0.560
ADH1C	ADH1B	psi-mi:“MI:0915”(physical association)	0.560
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
PRKCZ	POLRMT	psi-mi:“MI:0914”(association)	0.350
FNDC5	A2ML1	psi-mi:“MI:0914”(association)	0.350
ADH1C	ALOX12B	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): XYLT1 (Affinity Capture-MS), ADH1B (Affinity Capture-MS), ADH1B (Affinity Capture-MS), XYLT1 (Affinity Capture-MS), ADH1C (Affinity Capture-MS), ADH1B (Affinity Capture-MS), CALML3 (Affinity Capture-MS), POF1B (Affinity Capture-MS), ADH1C (Affinity Capture-MS), KPRP (Affinity Capture-MS), LGALS7B (Affinity Capture-MS), SERPINB2 (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM1 (Affinity Capture-MS)

ESM2 similar proteins: A0A2U1Q018, A1L4Y2, O46649, O57380, O74540, O97959, P00325, P00326, P00327, P00328, P00329, P07327, P08319, P14139, P22797, P25405, P25406, P26325, P28332, P28469, P40394, P41680, P41681, P41682, P78870, P80338, P80360, P80468, P80512, P80572, P81431, P81601, P86883, P86885, P93629, Q03505, Q0DWH1, Q0V7W6, Q5R1W2, 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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

998 predictions. Top by Δscore:

Variant	Effect	Δscore
4:99336775:TA:T	acceptor_gain	1.0000
4:99336777:C:CC	acceptor_gain	1.0000
4:99339576:CCT:C	donor_gain	1.0000
4:99339578:T:TA	donor_gain	1.0000
4:99339582:T:A	donor_gain	1.0000
4:99339713:AGCC:A	acceptor_loss	1.0000
4:99339715:CCTGA:C	acceptor_loss	1.0000
4:99339716:C:A	acceptor_loss	1.0000
4:99339716:C:CC	acceptor_gain	1.0000
4:99339717:T:C	acceptor_loss	1.0000
4:99344802:T:TA	donor_gain	1.0000
4:99344924:T:A	donor_gain	1.0000
4:99345087:CAG:C	acceptor_gain	1.0000
4:99345089:G:C	acceptor_gain	1.0000
4:99345089:G:GC	acceptor_gain	1.0000
4:99345092:CAA:C	acceptor_gain	1.0000
4:99345173:ACTT:A	donor_loss	1.0000
4:99345175:TTA:T	donor_loss	1.0000
4:99345176:TA:T	donor_loss	1.0000
4:99345177:A:AC	donor_gain	1.0000
4:99345177:A:C	donor_loss	1.0000
4:99345177:ACT:A	donor_gain	1.0000
4:99345178:C:CC	donor_gain	1.0000
4:99345178:CT:C	donor_gain	1.0000
4:99345178:CTC:C	donor_gain	1.0000
4:99345178:CTCA:C	donor_gain	1.0000
4:99345178:CTCAT:C	donor_gain	1.0000
4:99345181:A:AC	donor_gain	1.0000
4:99345182:T:C	donor_gain	1.0000
4:99345263:TCAC:T	acceptor_gain	1.0000

AlphaMissense

2444 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:99344994:G:C	S145R	0.993
4:99344994:G:T	S145R	0.993
4:99344996:T:G	S145R	0.993
4:99340669:A:C	S290R	0.992
4:99340669:A:T	S290R	0.992
4:99340671:T:G	S290R	0.992
4:99343035:A:C	C196W	0.992
4:99347126:A:G	C47R	0.992
4:99347752:C:G	R38P	0.992
4:99340577:C:T	G321E	0.991
4:99342987:A:C	C212W	0.991
4:99347059:T:A	E69V	0.990
4:99336772:G:T	R370S	0.989
4:99342826:G:C	S266W	0.988
4:99342989:A:G	C212R	0.988
4:99344906:A:G	C175R	0.988
4:99345257:A:T	V90D	0.988
4:99347755:A:T	V37D	0.988
4:99342952:T:A	D224V	0.987
4:99344890:C:T	G180D	0.987
4:99347124:A:C	C47W	0.987
4:99340690:A:C	C283W	0.986
4:99345190:G:C	C112W	0.986
4:99336771:C:G	R370P	0.985
4:99340596:A:G	W315R	0.985
4:99340596:A:T	W315R	0.985
4:99342953:C:G	D224H	0.985
4:99343033:G:T	A197D	0.985
4:99344995:C:A	S145I	0.985
4:99345192:A:G	C112R	0.985

dbSNP variants (sampled 300 via entrez): RS1000410422 (4:99350389 T>A), RS1000563194 (4:99344683 C>G), RS1000745822 (4:99351067 G>A), RS1000747411 (4:99338795 T>A), RS1000803812 (4:99349650 T>C), RS1000870720 (4:99344724 C>G,T), RS1001108935 (4:99344873 T>C), RS1001146118 (4:99337789 G>A), RS1001302631 (4:99343976 A>G), RS1001321159 (4:99337321 T>C), RS1001345468 (4:99351189 G>A), RS1001438837 (4:99350945 C>T), RS1001444989 (4:99351299 T>A), RS1001451806 (4:99338139 C>A,T), RS1001579196 (4:99350727 G>A)

Disease associations

OMIM: gene MIM:103730 | disease phenotypes: MIM:103780, MIM:556500, MIM:168600

GenCC curated gene-disease

Mondo (3): alcohol dependence (MONDO:0007079), Parkinson disease, mitochondrial (MONDO:0010796), late-onset Parkinson disease (MONDO:0008199)

Orphanet (1): Hereditary late-onset Parkinson disease (Orphanet:411602)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000298	Mask-like facies
HP:0000716	Depression
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0000751	Personality changes
HP:0001260	Dysarthria
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001426	Non-Mendelian inheritance
HP:0001621	Weak voice
HP:0002015	Dysphagia
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002172	Postural instability
HP:0002322	Resting tremor
HP:0002360	Sleep disturbance
HP:0002529	Neuronal loss in central nervous system
HP:0003581	Adult onset
HP:0003584	Late onset
HP:0003587	Insidious onset
HP:0003676	Progressive
HP:0003745	Sporadic
HP:0007311	Short stepped shuffling gait
HP:0011960	Substantia nigra gliosis
HP:0012332	Abnormal autonomic nervous system physiology
HP:0030955	Addictive alcohol use

GWAS associations

47 associations (top):

Study	Trait	p-value
GCST000245_14	Conduct disorder (maternal expressed emotions interaction)	3.000000e-06
GCST001011_1	Oral cavity and pharyngeal cancer	3.000000e-07
GCST001281_6	Alcohol dependence	1.000000e-08
GCST001883_1	Alcohol dependence	3.000000e-21
GCST003134_10	Cerebrospinal fluid clusterin levels	3.000000e-06
GCST003857_1	Oral cavity and pharyngeal cancer	2.000000e-15
GCST004711_13	Alcohol dependence	3.000000e-10
GCST004711_14	Alcohol dependence	5.000000e-10
GCST004711_15	Alcohol dependence	3.000000e-09
GCST004711_29	Alcohol dependence	2.000000e-06
GCST004711_3	Alcohol dependence	2.000000e-06
GCST004711_30	Alcohol dependence	2.000000e-06
GCST004711_37	Alcohol dependence	5.000000e-06
GCST004711_4	Alcohol dependence	2.000000e-06
GCST004711_43	Alcohol dependence	6.000000e-06
GCST004711_45	Alcohol dependence	6.000000e-06
GCST004712_16	Alcohol dependence	4.000000e-07
GCST004712_17	Alcohol dependence	7.000000e-07
GCST004712_18	Alcohol dependence	8.000000e-07
GCST004748_39	Lung cancer	2.000000e-06
GCST004756_2	Alcohol dependence	1.000000e-07
GCST004756_3	Alcohol dependence	2.000000e-08
GCST004886_13	Alcohol consumption	1.000000e-30
GCST004886_19	Alcohol consumption	2.000000e-09
GCST004886_2	Alcohol consumption	4.000000e-13
GCST004886_6	Alcohol consumption	3.000000e-19
GCST004887_1	Alcohol consumption in current drinkers	1.000000e-30
GCST004887_5	Alcohol consumption in current drinkers	1.000000e-09
GCST004990_2	Alcohol consumption over the past year	4.000000e-07
GCST006614_70	Total cholesterol levels	2.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0008342	parental emotion expression measurmement
EFO:0007835	alcohol dependence measurement
EFO:0004574	total cholesterol measurement
EFO:0009458	alcohol use disorder measurement
EFO:0009592	social interaction measurement
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0008343	sex interaction measurement
EFO:0004348	hematocrit
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564015	Parkinson Disease, Mitochondrial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2096668 (PROTEIN FAMILY), CHEMBL2363044 (PROTEIN COMPLEX GROUP), CHEMBL3285 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs13125415	Toxicity	3	ethanol	Alcohol abuse
rs698	Efficacy	3	cisplatin;cyclophosphamide	Ovarian Neoplasms
rs698	Efficacy	3	naltrexone	Alcohol abuse

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs698	ADH1C	3	2.50	2	cisplatin;cyclophosphamide;naltrexone
rs283411	ADH1C		0.00	0
rs283416	ADH1C		0.00	0
rs1662060	ADH1C		0.00	0
rs13125415	ADH1C	3	1.50	1	ethanol

ChEMBL bioactivities

6 potent at pChembl≥5 of 18 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.39	Ki	410	nM	CHEMBL48122
5.68	Ki	2100	nM	CHEMBL46655
5.34	Ki	4600	nM	CHEMBL45704
5.31	Ki	4900	nM	CHEMBL46293
5.28	Ki	5200	nM	CYCLOHEXYLFORMAMIDE
5.24	Ki	5800	nM	CHEMBL291214

PubChem BioAssay actives

6 with measured affinity, of 57 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
N-octan-2-ylformamide	34041: Inhibition of human alcohol dehydrogenase gamma2 activity	ki	0.4100	uM
N-cyclopropyl-N-heptylformamide	34041: Inhibition of human alcohol dehydrogenase gamma2 activity	ki	2.1000	uM
N-cyclopentyl-N-cyclopropylformamide	34041: Inhibition of human alcohol dehydrogenase gamma2 activity	ki	4.6000	uM
N-benzylformamide	34041: Inhibition of human alcohol dehydrogenase gamma2 activity	ki	4.9000	uM
N-cyclohexylformamide	34041: Inhibition of human alcohol dehydrogenase gamma2 activity	ki	5.2000	uM
N-(cyclohexylmethyl)formamide	34041: Inhibition of human alcohol dehydrogenase gamma2 activity	ki	5.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ethanol	affects response to substance, increases metabolic processing, increases chemical synthesis, increases oxidation, decreases reaction (+1 more)	6
Benzo(a)pyrene	increases mutagenesis, affects methylation, decreases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	3
Aflatoxin B1	affects expression, decreases expression	3
sodium arsenite	decreases expression	2
Acetaminophen	decreases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
Chenodeoxycholic Acid	affects cotreatment, decreases expression	2
Deoxycholic Acid	affects cotreatment, decreases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	2
Glycocholic Acid	affects cotreatment, decreases expression	2
Glycodeoxycholic Acid	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression	2
Cyclosporine	decreases expression, affects cotreatment	2
lasiocarpine	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	increases expression	1
chlortoluron	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
nefazodone	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
obeticholic acid	decreases expression	1
abrine	decreases expression	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	decreases expression	1
walrycin A	increases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 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)

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

Trial	Phase	Status	Title
NCT00000437	PHASE4	COMPLETED	Tobacco Dependence in Alcoholism Treatment (Nicotine Patch/Naltrexone)
NCT00000438	PHASE4	COMPLETED	Naltrexone Treatment for Alcoholism
NCT00000441	PHASE4	COMPLETED	Drug Therapy for Alcohol Detoxification
NCT00000442	PHASE4	COMPLETED	Naltrexone for Relapse Prevention
NCT00000444	PHASE4	COMPLETED	Timing of Smoking Intervention in Alcohol Treatment (Nicotine Patch)
NCT00000445	PHASE4	COMPLETED	Use of Naltrexone in a Clinical Setting
NCT00000447	PHASE4	COMPLETED	Behavioral/Drug Therapy for Alcohol-Nicotine Dependence (Naltrexone/Nicotine Patch)
NCT00000448	PHASE4	COMPLETED	Naltrexone Treatment for Alcoholic Women
NCT00000449	PHASE4	COMPLETED	Behavior and Naltrexone Treatment for Alcoholics
NCT00000450	PHASE4	COMPLETED	Naltrexone Maintenance Treatment of Alcoholism
NCT00000452	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Dependence
NCT00000454	PHASE4	COMPLETED	Smoking Cessation in Alcoholism Treatment
NCT00000455	PHASE4	COMPLETED	Naltrexone for Early Problem Drinkers
NCT00000456	PHASE4	COMPLETED	Behavioral Therapy Plus Naltrexone for Alcoholism
NCT00004551	PHASE4	COMPLETED	Behavioral Counseling for Alcohol Dependent Smokers (Nicotine Patch)
NCT00004554	PHASE4	COMPLETED	Sertraline for Alcohol Dependence and Depression
NCT00006203	PHASE4	COMPLETED	Naltrexone, Craving, and Drinking
NCT00006204	PHASE4	COMPLETED	Drug Treatment for Depressed Alcoholics (Naltrexone/Fluoxetine)
NCT00006449	PHASE4	COMPLETED	Post-Treatment Effects of Naltrexone
NCT00006489	PHASE4	COMPLETED	Treatment for Alcoholism and Post-Traumatic Stress Disorder (Naltrexone)
NCT00018824	PHASE4	COMPLETED	Treating Alcohol Use In Older Adults With Depression
NCT00044434	PHASE4	COMPLETED	Bupropion as a Smoking Cessation Aid in Alcoholics
NCT00064844	PHASE4	COMPLETED	Combination Nicotine Replacement for Alcoholic Smokers
NCT00082199	PHASE4	COMPLETED	Study of Aripiprazole in Subjects With Alcoholism
NCT00115037	PHASE4	COMPLETED	Managing Alcoholism in People Who Do Not Respond to Naltrexone
NCT00120601	PHASE4	UNKNOWN	Trial for the Treatment of Alcohol Dependence
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148031	PHASE4	COMPLETED	Improving Hepatitis C Treatment in Injection Drug Users
NCT00159107	PHASE4	COMPLETED	Integrative Therapy in Alcoholism
NCT00167687	PHASE4	COMPLETED	Prazosin Alcohol Dependence IVR Study
NCT00223275	PHASE4	COMPLETED	Naltrexone for Bipolar Disorder and Alcohol Dependence
NCT00226109	PHASE4	SUSPENDED	Clinical Trial Studying the Effects of Spironolactone on Heart and Skeletal Muscle Function in Chronic Alcoholics
NCT00246441	PHASE4	COMPLETED	Paroxetine for Comorbid Social Anxiety Disorder and Alcoholism
NCT00249379	PHASE4	TERMINATED	Study of Acamprosate to Prevent Alcohol Relapse in Criminal Justice Supervisees
NCT00261872	PHASE4	COMPLETED	Treatment of Patients With Alcoholism and Attention Deficit Disorder
NCT00317031	PHASE4	COMPLETED	Individually Adapted Therapy of Alcoholism
NCT00325182	PHASE4	COMPLETED	The Effects of Levetiracetam on Alcohol Dependent Subjects
NCT00329407	PHASE4	COMPLETED	The Effects of Topiramate on Alcohol Use in Alcohol Dependent Subjects
NCT00330174	PHASE4	COMPLETED	Acamprosate in Alcoholics With Comorbid Anxiety or Depression
NCT00352469	PHASE4	COMPLETED	Trial of Seroquel SR for Alcohol Dependence and Comorbid Anxiety