ALDH1A3

Summary

ALDH1A3 (aldehyde dehydrogenase 1 family member A3, HGNC:409) is a protein-coding gene on chromosome 15q26.3, encoding Retinaldehyde dehydrogenase 3 (P47895). Catalyzes the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively.

This gene encodes an aldehyde dehydrogenase enzyme that uses retinal as a substrate. Mutations in this gene have been associated with microphthalmia, isolated 8, and expression changes have also been detected in tumor cells. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 220 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated anophthalmia-microphthalmia syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 180 total — 13 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:409
Approved symbol	ALDH1A3
Name	aldehyde dehydrogenase 1 family member A3
Location	15q26.3
Locus type	gene with protein product
Status	Approved
Aliases	RALDH3
Ensembl gene	ENSG00000184254
Ensembl biotype	protein_coding
OMIM	600463
Entrez	220

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000329841, ENST00000346623, ENST00000557963, ENST00000558033, ENST00000558568, ENST00000558869, ENST00000560555, ENST00000561338, ENST00000856095, ENST00000856096, ENST00000916365, ENST00000916366, ENST00000916367, ENST00000953140

RefSeq mRNA: 2 — MANE Select: NM_000693 NM_000693, NM_001293815

CCDS: CCDS10389, CCDS76794

Canonical transcript exons

ENST00000329841 — 13 exons

Exon	Start	End
ENSE00001296001	100898083	100898185
ENSE00001300123	100895933	100896046
ENSE00001325178	100892510	100892639
ENSE00001657807	100908408	100908482
ENSE00001949241	100914701	100916626
ENSE00001954388	100879831	100880006
ENSE00002515998	100907121	100907278
ENSE00003470503	100905523	100905687
ENSE00003519906	100887572	100887712
ENSE00003528658	100900575	100900759
ENSE00003588955	100892945	100893006
ENSE00003598646	100893954	100894082
ENSE00003682659	100885267	100885371

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 99.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.7510 / max 2127.5010, expressed in 1259 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148929	37.5029	1255
148935	0.0982	39
148934	0.0620	18
148928	0.0464	12
148926	0.0211	5
148927	0.0204	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	99.59	gold quality
pigmented layer of retina	UBERON:0001782	98.09	gold quality
parietal pleura	UBERON:0002400	97.06	gold quality
esophagus squamous epithelium	UBERON:0006920	96.96	gold quality
parotid gland	UBERON:0001831	96.65	gold quality
prostate gland	UBERON:0002367	96.59	gold quality
germinal epithelium of ovary	UBERON:0001304	95.99	gold quality
periodontal ligament	UBERON:0008266	95.96	gold quality
urethra	UBERON:0000057	95.65	gold quality
minor salivary gland	UBERON:0001830	95.55	gold quality
epithelium of esophagus	UBERON:0001976	95.36	gold quality
cauda epididymis	UBERON:0004360	95.18	gold quality
saliva-secreting gland	UBERON:0001044	95.00	gold quality
pleura	UBERON:0000977	94.52	gold quality
seminal vesicle	UBERON:0000998	94.48	gold quality
islet of Langerhans	UBERON:0000006	94.11	gold quality
mouth mucosa	UBERON:0003729	93.85	gold quality
choroid plexus epithelium	UBERON:0003911	93.61	gold quality
omental fat pad	UBERON:0010414	93.50	gold quality
peritoneum	UBERON:0002358	93.49	gold quality
oral cavity	UBERON:0000167	93.41	gold quality
sperm	CL:0000019	93.21	gold quality
caput epididymis	UBERON:0004358	93.05	gold quality
epithelium of mammary gland	UBERON:0003244	92.45	gold quality
mucosa of urinary bladder	UBERON:0001259	92.24	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.21	gold quality
mammary duct	UBERON:0001765	91.97	gold quality
visceral pleura	UBERON:0002401	91.33	gold quality
male germ cell	CL:0000015	90.87	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	28219.26
E-GEOD-86618	yes	2929.54
E-MTAB-8559	yes	1356.87
E-CURD-53	yes	864.61
E-MTAB-10855	yes	778.99
E-GEOD-134144	yes	37.42
E-MTAB-5061	yes	26.82
E-CURD-46	yes	20.19
E-HCAD-4	yes	16.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CTCF, GSX2, TP53, VAX2

miRNA regulators (miRDB)

96 targeting ALDH1A3, 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-3925-3P	100.00	69.95	1237
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4799-5P	99.82	70.60	2663

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Gene duplication event that gave rise to Aldh1a1 and Aldh1a2 was more recent than the duplication event that gave rise to Aldh1a3. (PMID:19478994)
• these results indicate that the regulation of the retinoic acid metabolism in the epidermis involves transcriptional activation of ALDH1A3, possibly representing a positive feedback loop, which enhances the effect of exogenous retinoic acid. (PMID:20709019)
• ALDH1A3 expression in patient breast tumors correlates significantly with tumor grade, metastasis, and cancer stage (PMID:21280157)
• ALDH1A3 transcripts are detected at high levels in luminal progenitor-enriched fractions obtained from short-term adherent cultures of freshly isolated normal human mammary cells. (PMID:22131125)
• The effects of phenotypic and morphological alterations by DEAB on oral keratinocytes are mainly consequent to the inhibition of ALDH1A3 activity. (PMID:23250514)
• Homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families, is reported. (PMID:23312594)
• The methylation status of Homeobox A9 (HOXA9), ISL LIM homeobox 1 (ISL1) and Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) was significantly associated with decreased gene expression levels (PMID:23436614)
• Results show that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems. (PMID:23591992)
• Our data support the very recent and independent identification of ALDH1A3 as a disease gene in microphthalmia. (PMID:23646827)
• two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. (PMID:23650391)
• Nine individuals, from one inbred kindred, segregating isolated A/M with orbital cysts were homozygous for a missense mutation in the gene encoding the A3 isoform of the ALDH1A3. (PMID:23881059)
• ALDH1A3 expression determines the stem cell-like cellular states in EGFR-mutant non-small cell lung cancer; a novel mechanism of acquired resistance to erlotinib can be targeted with the natural polyphenol silibinin. (PMID:24047698)
• ALDH1A3 may be upregulated in pancreatic cancer (PMID:24053169)
• Novel ALDH1A3 mutations identified in the present study confirm the pivotal role of ALDH1A3 in human eye development. (PMID:24568872)
• Mutations in ALDH1A3 represent a frequent cause of microphthalmia/anophthalmia in consanguineous families. (PMID:24777706)
• At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance (PMID:24884875)
• High ALDH1A3 expression is associated with non-small cell lung cancer. (PMID:24907115)
• ALDH1A3 induces differential RA signaling in breast cancer cells which affects the rate of breast cancer progression. (PMID:25106087)
• Among unique genes up-regulated by Y15 in Lovo-1 and K1 resistant cells, a stem cell marker-ALDH1A3-was detected to be up-regulated >twofold. (PMID:25656374)
• Increased hypermethylation of ALDH1A3 is associated with Glioblastoma. (PMID:25684492)
• the distribution of RALDH1, RALDH2, and RALDH3 in the postnatal eye was determined. (PMID:25793304)
• we demonstrated that a specific ALDH isoform, namely ALDH1A3, is enriched in chemoresistant mesothelioma cell subpopulations (PMID:25868979)
• ALDH1A3 is a target of miR-187 in human prostate cancer. (PMID:25969992)
• Whole-exome sequencing in a South American cohort links ALDH1A3, FOXN1 and RARB/retinoic acid regulation pathways to autism spectrum disorders. (PMID:26352270)
• ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro. (PMID:26575197)
• the prevalence of ALDH1A3(+)/CD44(+) tumor cells in breast cancer is significantly associated with worse prognostic factors and favors a poor prognosis (PMID:26687806)
• this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families (PMID:26873617)
• high transcription activities of ALDH1A2, ALDH1A3 and ALDH1L1 predicted worsen overall survival in gastric cancer patients (PMID:27015121)
• ALDH1A3 is a poor prognostic factor for patients with intrahepatic cholangiocarcinoma who underwent hepatectomy and in those with advanced intrahepatic cholangiocarcinoma receiving chemotherapy. (PMID:27076629)
• Data show that retinoic acid receptor responder 1 (RARRES1) expression is subtype-dependent and regulated by DNA methylation and the expression of aldehyde dehydrogenase 1A3 (ALDH1A3). (PMID:27286452)
• our findings define a FOXD1-ALDH1A3 pathway in controling the clonogenic and tumorigenic potential of mesenchymal glioma stem-like cells in glioblastoma tumors (PMID:27569208)
• Here the authors report the first crystal structure of human ALDH1A3 complexed with NAD(+) and the product all-trans retinoic acid (REA). The tetrameric ALDH1A3 folds into a three domain-based architecture highly conserved along the ALDHs family. The structural analysis revealed two different and coupled conformations for NAD(+) and REA that the authors propose to represent two snapshots along the catalytic cycle. (PMID:27759097)
• these findings ascribe a novel function for ALDH1A3 in an aggressive glioma stem cells phenotype via the up-regulation of tissue transglutaminase (PMID:28423611)
• we looked up our single center primary prostate cancer post-operative follow-up data and suggested that the high level ALDH1A3 expression could predict the poor progression-free survival in a 158-patient cohort. We concluded that ALDH1A3, localized in luminal layer in prostate epithelium, is highly expressed in prostate cancer (PMID:28443495)
• Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. (PMID:28581514)
• ALDH1A3 is the key isoform that contributed to Aldefluor positivity in cell lines. Knocking down ALDH1A3 in different cancer cells conferred opposite phenotypes due to differential effects on CXCR4 expression. There was a significant negative correlation between ALDH1A3 and CXCR4 in 58 human cell lines. (PMID:29235568)
• Data indicate that aldehyde dehydrogenase 1A3 (ALDH1A3), that is directly involved in therapy resistance of glioblastoma, is regulated by autophagy during chemotherapy. (PMID:29306018)
• Study using human SH-SY5Y neuroblastoma and 293T cells and transgenic mouse model show that CHD7 directly regulates expression of retinoic acid synthetic enzyme ALDH1A3. Results indicate that ALDH1A3 acts with CHD7 in a common genetic pathway to regulate inner ear development, providing insights for exploration of the pathogenic mechanisms underlying CHARGE syndrome. (PMID:29467333)
• Targeting USP22 represents a potential therapeutic approach to suppress cancer-initiating cells (CIC) in lung adenocarcinoma partially through downregulation of ALDH1A3 expression. (PMID:29720480)
• ALDH1A3 suppression could be one of PPARG tumor suppressive function. This study provides a better understanding of the role of PPARG in lung cancer. (PMID:29873276)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aldh1a3	ENSDARG00000076933
mus_musculus	Aldh1a3	ENSMUSG00000015134
rattus_norvegicus	Aldh1a3	ENSRNOG00000052070

Paralogs (17): ALDH3B1 (ENSG00000006534), ALDH3A2 (ENSG00000072210), ALDH3A1 (ENSG00000108602), ALDH2 (ENSG00000111275), ALDH5A1 (ENSG00000112294), ALDH8A1 (ENSG00000118514), ALDH6A1 (ENSG00000119711), ALDH1A2 (ENSG00000128918), ALDH3B2 (ENSG00000132746), ALDH1L2 (ENSG00000136010), ALDH1B1 (ENSG00000137124), ALDH9A1 (ENSG00000143149), ALDH1L1 (ENSG00000144908), ALDH4A1 (ENSG00000159423), ALDH16A1 (ENSG00000161618), ALDH7A1 (ENSG00000164904), ALDH1A1 (ENSG00000165092)

Protein

Protein identifiers

Retinaldehyde dehydrogenase 3 — P47895 (reviewed: P47895)

Alternative names: Aldehyde dehydrogenase 6, Aldehyde dehydrogenase family 1 member A3

All UniProt accessions (5): P47895, H0Y2X5, H0YKF9, H0YLT1, H0YNQ3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively. High specificity for all-trans-retinal as substrate, can also accept acetaldehyde as substrate in vitro but with lower affinity. Required for the biosynthesis of normal levels of retinoate in the embryonic ocular and nasal regions; a critical lipid in the embryonic development of the eye and the nasal region.

Subunit / interactions. Homotetramer.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed at low levels in many tissues and at higher levels in salivary gland, stomach, and kidney.

Disease relevance. Microphthalmia, isolated, 8 (MCOP8) [MIM:615113] A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Cofactor metabolism; retinol metabolism.

Similarity. Belongs to the aldehyde dehydrogenase family.

RefSeq proteins (2): NP_000684, NP_001280744 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015590	Aldehyde_DH_dom	Domain
IPR016160	Ald_DH_CS_CYS	Conserved_site
IPR016161	Ald_DH/histidinol_DH	Homologous_superfamily
IPR016162	Ald_DH_N	Homologous_superfamily
IPR016163	Ald_DH_C	Homologous_superfamily
IPR029510	Ald_DH_CS_GLU	Conserved_site

Pfam: PF00171

Enzyme classification (BRENDA):

• EC 1.2.1.5 — aldehyde dehydrogenase [NAD(P)+] (BRENDA: 19 organisms, 218 substrates, 93 inhibitors, 198 Km, 45 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
NAD+	0.003–35	30
NADP+	0.01–260	22
BENZALDEHYDE	0.013–4.15	17
ACETALDEHYDE	0.0002–393.4	16
PROPANAL	0.0004–19.06	14
CHLOROACETALDEHYDE	0.01–0.46	7
3,4-DIHYDROXYPHENYLACETALDEHYDE	0.0004–0.015	5
2-BROMOBENZALDEHYDE	0.012–0.379	4
2-FLUOROBENZALDEHYDE	0.008–0.822	4
PROPIONALDEHYDE	0.46–12	4
2-CHLOROBENZALDEHYDE	0.006–0.063	3
4-BROMOBENZALDEHYDE	0.039–0.617	3
4-CHLOROBENZALDEHYDE	0.031–1.159	3
4-FLUOROBENZALDEHYDE	0.012–2.057	3
4-IODOBENZALDEHYDE	0.081–1.103	3

Catalyzed reactions (Rhea), 3 shown:

• retinal + NAD(+) + H2O = retinoate + NADH + 2 H(+) (RHEA:16177)
• all-trans-retinal + NAD(+) + H2O = all-trans-retinoate + NADH + 2 H(+) (RHEA:42080)
• all-trans-13,14-dihydroretinal + NAD(+) + H2O = all-trans-13,14-dihydroretinoate + NADH + 2 H(+) (RHEA:75119)

UniProt features (73 total): strand 27, helix 20, sequence variant 11, binding site 5, turn 2, active site 2, initiator methionine 1, chain 1, site 1, modified residue 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
7QK9	X-RAY DIFFRACTION	1.78
7QK8	X-RAY DIFFRACTION	1.89
9QZE	X-RAY DIFFRACTION	2.01
7QK7	X-RAY DIFFRACTION	2.29
6TGW	X-RAY DIFFRACTION	2.8
5FHZ	X-RAY DIFFRACTION	2.9
6TRY	X-RAY DIFFRACTION	2.9
7A6Q	X-RAY DIFFRACTION	2.95
6S6W	X-RAY DIFFRACTION	3.25
6TE5	X-RAY DIFFRACTION	3.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P47895-F1	95.79	0.93

Functional residue map

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

Catalytic / active sites (3): 181 (transition state stabilizer); 280 (proton acceptor); 314 (nucleophile)

Ligand- & substrate-binding residues (5): 204; 207; 257–262; 361; 411

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5365859	RA biosynthesis pathway
R-HSA-9927418	Developmental Lineage of Mammary Gland Luminal Epithelial Cells
R-HSA-9927426	Developmental Lineage of Mammary Gland Alveolar Cells
R-HSA-9927432	Developmental Lineage of Mammary Gland Myoepithelial Cells
R-HSA-9938206	Developmental Lineage of Mammary Stem Cells
R-HSA-162582	Signal Transduction
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-9006931	Signaling by Nuclear Receptors

MSigDB gene sets: 316 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MODULE_93, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_REFLEX, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, GOBP_FOREBRAIN_DEVELOPMENT

GO Biological Process (21): optic cup morphogenesis involved in camera-type eye development (GO:0002072), retinoic acid biosynthetic process (GO:0002138), aldehyde metabolic process (GO:0006081), apoptotic process (GO:0006915), locomotory behavior (GO:0007626), nucleus accumbens development (GO:0021768), embryonic camera-type eye development (GO:0031076), inner ear morphogenesis (GO:0042472), retinol metabolic process (GO:0042572), retinoic acid metabolic process (GO:0042573), retinal metabolic process (GO:0042574), positive regulation of apoptotic process (GO:0043065), embryonic eye morphogenesis (GO:0048048), neuromuscular process controlling balance (GO:0050885), protein homotetramerization (GO:0051289), righting reflex (GO:0060013), olfactory pit development (GO:0060166), face development (GO:0060324), Harderian gland development (GO:0070384), lipid metabolic process (GO:0006629), nose development (GO:0043584)

GO Molecular Function (8): retinal dehydrogenase (NAD+) activity (GO:0001758), aldehyde dehydrogenase (NAD+) activity (GO:0004029), aldehyde dehydrogenase [NAD(P)+] activity (GO:0004030), protein homodimerization activity (GO:0042803), thyroid hormone binding (GO:0070324), NAD+ binding (GO:0070403), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor (GO:0016620)

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

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Developmental Lineages of the Mammary Gland	4
Signaling by Retinoic Acid	1
Signaling by Nuclear Receptors	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
retinoid metabolic process	3
hormone metabolic process	2
olefinic compound metabolic process	2
anatomical structure development	2
cellular anatomical structure	2
morphogenesis of embryonic epithelium	1
embryonic camera-type eye formation	1
diterpenoid biosynthetic process	1
retinoic acid metabolic process	1
monocarboxylic acid biosynthetic process	1
metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
behavior	1
striatum development	1
limbic system development	1
neural nucleus development	1
camera-type eye development	1
embryonic organ development	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
primary alcohol metabolic process	1
monocarboxylic acid metabolic process	1
aldehyde metabolic process	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
embryonic organ morphogenesis	1
eye morphogenesis	1
musculoskeletal movement	1
neuromuscular process	1
protein homooligomerization	1
protein tetramerization	1
reflex	1
nose development	1
head development	1
gland development	1
primary metabolic process	1

Protein interactions and networks

STRING

4024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALDH1A3	RDH12	Q96NR8	847
ALDH1A3	CYP26A1	O43174	720
ALDH1A3	RDH10	Q8IZV5	690
ALDH1A3	CYP26B1	Q9NR63	689
ALDH1A3	STRA6	Q9BX79	657
ALDH1A3	CYP26C1	Q6V0L0	640
ALDH1A3	RARS1	P54136	633
ALDH1A3	RARB	P10826	608
ALDH1A3	RPE65	Q16518	600
ALDH1A3	RARG	P13631	586
ALDH1A3	RARA	P10276	585
ALDH1A3	ALDH18A1	P54886	574
ALDH1A3	RDH5	Q92781	572
ALDH1A3	RBP1	P09455	571
ALDH1A3	CD44	P16070	537

IntAct

54 interactions, top by confidence:

A	B	Type	Score
LSM3	LSM1	psi-mi:“MI:0914”(association)	0.950
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
CFAP46	GAPDHS	psi-mi:“MI:0914”(association)	0.530
DHDH	ATRN	psi-mi:“MI:0914”(association)	0.530
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
TRPV2	ALDH1A3	psi-mi:“MI:0915”(physical association)	0.370
PDE4DIP	A2ML1	psi-mi:“MI:0914”(association)	0.350
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
GORASP1	CLASP2	psi-mi:“MI:0914”(association)	0.350
ITGA9	IGLL5	psi-mi:“MI:0914”(association)	0.350
SMOX	ALDH1A3	psi-mi:“MI:0914”(association)	0.350
VAV1		psi-mi:“MI:0914”(association)	0.350
SH2D3C	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
CAV1	ACOT7	psi-mi:“MI:0914”(association)	0.350
RAB5A	EIF3CL	psi-mi:“MI:0914”(association)	0.350
GRB10	POLRMT	psi-mi:“MI:0914”(association)	0.350
PRKD1		psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
FAM24B	SHTN1	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
PTH2R	METTL15	psi-mi:“MI:0914”(association)	0.350
SRRT	A2ML1	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
ST6GALNAC6	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (68): ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-Western), USP9X (Affinity Capture-Western), USP9X (Reconstituted Complex), ALDH1A3 (Biochemical Activity), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS), ALDH1A3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E3T3B5, A0A0E3T552, A0A2I7G3B0, A0A5C1REZ4, A7ZI51, B0CKN3, B1J0W5, B3VMC0, B6ECN9, B7M2V6, B7MCD1, B7N8L4, B7NK50, B8M9K4, C0P9J6, C6KEM4, G5DDC2, H8ZPX2, O04895, O06837, O14293, O24174, O59808, O74187, O93344, O94788, P13601, P17202, P28237, P42269, P42757, P47895, Q0TKW0, Q28399, Q29490, Q32FQ5, Q40024, Q56R04, Q62148, Q63639

Diamond homologs: A0A0E3T3B5, A0A0E3T552, A0A2I7G3B0, A0B2F6, A4JJG5, A4VKC2, A4XPI6, A5WA96, A6VEI4, A6ZR27, A8GBX8, A9AN00, B0KN18, B1J2K9, B1JSQ9, B1K708, B1Z033, B2FQ90, B3VMC0, B4EHJ1, B6ECN9, B7V5R4, C0P9J6, C3K3D2, C5I9X1, C6DKY5, C6KEM4, G5DDC2, H8ZPX2, O04895, O14293, O24174, O34660, O35945, O59808, O74187, O93344, O94788, P00352, P05091

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ALDH1A3	“down-regulates quantity”	retinal	“chemical modification”
ALDH1A3	“up-regulates quantity”	“all-trans-retinoic acid”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	11
Uncertain significance	50
Likely benign	53
Benign	36

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1372977	NM_000693.4(ALDH1A3):c.439_458del (p.Trp147fs)	Pathogenic
1701914	NM_000693.4(ALDH1A3):c.1444del (p.Met482fs)	Pathogenic
1801374	NM_000693.4(ALDH1A3):c.550del (p.Leu184fs)	Pathogenic
1803002	NM_000693.4(ALDH1A3):c.566G>A (p.Trp189Ter)	Pathogenic
1803003	NM_000693.4(ALDH1A3):c.100-2A>G	Pathogenic
1803004	NM_000693.4(ALDH1A3):c.1233+2T>C	Pathogenic
40203	NM_000693.4(ALDH1A3):c.265C>T (p.Arg89Cys)	Pathogenic
40204	NM_000693.4(ALDH1A3):c.1477G>C (p.Ala493Pro)	Pathogenic
40205	NM_000693.4(ALDH1A3):c.475+1G>T	Pathogenic
449288	NM_000693.4(ALDH1A3):c.537+5G>A	Pathogenic
91908	NM_000693.4(ALDH1A3):c.211G>A (p.Val71Met)	Pathogenic
978214	NM_000693.4(ALDH1A3):c.287G>A (p.Arg96His)	Pathogenic
978215	NM_000693.4(ALDH1A3):c.709G>A (p.Gly237Arg)	Pathogenic
1049955	NM_000693.4(ALDH1A3):c.845G>T (p.Gly282Val)	Likely pathogenic
1802995	NM_000693.4(ALDH1A3):c.1144G>A (p.Gly382Arg)	Likely pathogenic
1802996	NM_000693.4(ALDH1A3):c.434C>T (p.Ala145Val)	Likely pathogenic
1802998	NM_000693.4(ALDH1A3):c.845G>C (p.Gly282Ala)	Likely pathogenic
1802999	NM_000693.4(ALDH1A3):c.1459A>G (p.Arg487Gly)	Likely pathogenic
212709	NM_000693.4(ALDH1A3):c.1514T>C (p.Ile505Thr)	Likely pathogenic
3064143	NM_000693.4(ALDH1A3):c.1105A>T (p.Ile369Phe)	Likely pathogenic
3777064	NM_000693.4(ALDH1A3):c.172dup (p.Glu58fs)	Likely pathogenic
4279036	NM_000693.4(ALDH1A3):c.1334C>T (p.Thr445Ile)	Likely pathogenic
498816	NM_000693.4(ALDH1A3):c.184G>T (p.Glu62Ter)	Likely pathogenic
585293	NM_000693.4(ALDH1A3):c.1436G>A (p.Gly479Asp)	Likely pathogenic

SpliceAI

2036 predictions. Top by Δscore:

Variant	Effect	Δscore
15:100885260:T:TA	acceptor_gain	1.0000
15:100887709:GGCC:G	donor_gain	1.0000
15:100887710:GCC:G	donor_gain	1.0000
15:100887710:GCCG:G	donor_gain	1.0000
15:100887713:G:GG	donor_gain	1.0000
15:100892929:T:G	acceptor_gain	1.0000
15:100893952:AGT:A	acceptor_gain	1.0000
15:100893953:GTG:G	acceptor_gain	1.0000
15:100895928:CCCA:C	acceptor_loss	1.0000
15:100895929:CCAG:C	acceptor_loss	1.0000
15:100895931:AGGCC:A	acceptor_gain	1.0000
15:100895932:GGCCG:G	acceptor_gain	1.0000
15:100896044:GAG:G	donor_gain	1.0000
15:100896044:GAGG:G	donor_loss	1.0000
15:100896045:AGG:A	donor_loss	1.0000
15:100896047:G:T	donor_loss	1.0000
15:100896048:T:A	donor_loss	1.0000
15:100903344:A:AG	acceptor_gain	1.0000
15:100905652:G:GT	donor_gain	1.0000
15:100905684:GGAG:G	donor_gain	1.0000
15:100905684:GGAGG:G	donor_loss	1.0000
15:100905685:G:GT	donor_gain	1.0000
15:100905685:GAGGT:G	donor_loss	1.0000
15:100905688:G:GA	donor_loss	1.0000
15:100905689:T:G	donor_loss	1.0000
15:100907109:A:AG	acceptor_gain	1.0000
15:100907110:A:G	acceptor_gain	1.0000
15:100907119:A:AG	acceptor_gain	1.0000
15:100907120:G:GG	acceptor_gain	1.0000
15:100907274:GTCTG:G	donor_gain	1.0000

AlphaMissense

3348 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:100893959:C:A	N181K	0.997
15:100893959:C:G	N181K	0.997
15:100905644:T:A	V397D	0.997
15:100907124:T:C	F413L	0.997
15:100907126:C:A	F413L	0.997
15:100907126:C:G	F413L	0.997
15:100898157:C:A	N285K	0.996
15:100898157:C:G	N285K	0.996
15:100907151:T:C	F422L	0.996
15:100907153:C:A	F422L	0.996
15:100907153:C:G	F422L	0.996
15:100907203:T:C	L439P	0.996
15:100907269:G:A	G461E	0.996
15:100908445:T:C	F477L	0.996
15:100908447:T:A	F477L	0.996
15:100908447:T:G	F477L	0.996
15:100908467:G:A	G484E	0.996
15:100898168:T:A	V289E	0.995
15:100900656:T:A	V322E	0.995
15:100907200:G:A	G438E	0.995
15:100907208:G:C	A441P	0.995
15:100907277:T:A	W464R	0.995
15:100907277:T:C	W464R	0.995
15:100893960:T:C	F182L	0.994
15:100893962:C:A	F182L	0.994
15:100893962:C:G	F182L	0.994
15:100898144:T:C	L281P	0.994
15:100900691:A:C	S334R	0.994
15:100900693:C:A	S334R	0.994
15:100900693:C:G	S334R	0.994

dbSNP variants (sampled 300 via entrez): RS1000015455 (15:100878448 C>T), RS1000034230 (15:100915153 CCT>C), RS1000178505 (15:100883302 A>C), RS1000201598 (15:100898072 C>G,T), RS1000337993 (15:100888405 A>T), RS1000397374 (15:100916326 G>A,C), RS1000501904 (15:100899526 C>T), RS1000520454 (15:100894224 G>A), RS1000532644 (15:100899363 G>A,T), RS1000533237 (15:100910985 G>A), RS1000781277 (15:100892844 T>C), RS1000833866 (15:100893161 T>G), RS1000989820 (15:100889017 T>C), RS1000997519 (15:100887139 C>T), RS1001135682 (15:100904873 C>G,T)

Disease associations

OMIM: gene MIM:600463 | disease phenotypes: MIM:615113, MIM:209850, MIM:614429

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated anophthalmia-microphthalmia syndrome	Definitive	Autosomal recessive
isolated microphthalmia 8	Strong	Autosomal recessive

Mondo (6): isolated microphthalmia 8 (MONDO:0014050), microphthalmia (MONDO:0021129), autism (MONDO:0005260), isolated anophthalmia-microphthalmia syndrome (MONDO:0016764), esophageal atresia (MONDO:0001044), ventricular septal defect (MONDO:0002070)

Orphanet (2): Isolated microphthalmia-anophthalmia-coloboma (Orphanet:2542), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

16 total (19 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000480	Retinal coloboma
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000528	Anophthalmia
HP:0000541	Retinal detachment
HP:0000568	Microphthalmia
HP:0000609	Optic nerve hypoplasia
HP:0000610	Abnormal choroid morphology
HP:0000621	Entropion
HP:0003577	Congenital onset
HP:0007703	Abnormal retinal pigmentation
HP:0008499	High hypermetropia
HP:0011478	True anophthalmia
HP:0012745	Short palpebral fissure
HP:0034311	Hypoplastic optic chiasm
HP:0000717	Autism
HP:0002032	Esophageal atresia
HP:0001629	Ventricular septal defect

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003989_29	Chin dimples	9.000000e-13
GCST009724_63	Vertical cup-disc ratio (multi-trait analysis)	2.000000e-20

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006939	cup-to-disc ratio measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004933	Esophageal Atresia	C06.198.330; C06.405.117.260; C16.131.314.330
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D008850	Microphthalmos	C11.250.566; C16.131.384.666

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3542434 (PROTEIN FAMILY), CHEMBL3579 (SINGLE PROTEIN)

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

ChEMBL bioactivities

98 potent at pChembl≥5 of 113 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.47	IC50	34	nM	CHEMBL4876602
7.30	IC50	50	nM	CHEMBL4861872
7.22	IC50	60	nM	CHEMBL4859904
7.14	IC50	73	nM	CHEMBL4848258
7.05	IC50	90	nM	CHEMBL4213331
7.05	IC50	89	nM	CHEMBL4875157
7.04	IC50	91	nM	CHEMBL4848831
7.02	IC50	95	nM	CHEMBL4855442
7.00	IC50	100	nM	CHEMBL4849624
6.96	IC50	109	nM	CHEMBL4847114
6.95	IC50	112	nM	CHEMBL4874309
6.92	IC50	120	nM	CHEMBL4210115
6.92	Ki	120	nM	CHEMBL4642789
6.92	IC50	119	nM	CHEMBL4876076
6.89	IC50	130	nM	CHEMBL4214509
6.89	IC50	130	nM	CHEMBL4217452
6.89	IC50	128	nM	CHEMBL4862833
6.89	IC50	130	nM	CHEMBL4863668
6.85	IC50	140	nM	CHEMBL4873315
6.82	IC50	150	nM	CHEMBL4873090
6.77	IC50	170	nM	CHEMBL1349972
6.77	IC50	170	nM	CHEMBL4216790
6.77	IC50	170	nM	CHEMBL4205216
6.76	IC50	174	nM	CHEMBL4846491
6.75	IC50	180	nM	CHEMBL4213859
6.73	IC50	187	nM	CHEMBL3276621
6.70	IC50	200	nM	CHEMBL4852411
6.62	IC50	240	nM	CHEMBL4868666
6.60	IC50	250	nM	CHEMBL4846203
6.58	Ki	261	nM	CHEMBL3276621
6.58	IC50	260	nM	CHEMBL5075900
6.57	IC50	270	nM	CHEMBL4072941
6.57	IC50	270	nM	CHEMBL1589630
6.52	IC50	300	nM	CHEMBL5086460
6.51	IC50	310	nM	CHEMBL5090970
6.41	IC50	390	nM	CHEMBL4217294
6.40	IC50	400	nM	CHEMBL4099822
6.34	Ki	460	nM	CHEMBL5083058
6.32	IC50	480	nM	CHEMBL4849586
6.30	IC50	500	nM	CHEMBL4857551
6.28	IC50	520	nM	CHEMBL4877915
6.27	Ki	540	nM	CHEMBL4456676
6.26	IC50	550	nM	CHEMBL4205099
6.26	IC50	550	nM	CHEMBL5087589
6.23	IC50	590	nM	CHEMBL4862473
6.22	IC50	600	nM	CHEMBL4865571
6.22	IC50	600	nM	CHEMBL4859854
6.21	IC50	610	nM	CHEMBL4218404
6.20	IC50	630	nM	CHEMBL5083058
6.18	IC50	660	nM	CHEMBL4642789

PubChem BioAssay actives

115 with measured affinity, of 336 total; 50 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
1-methyl-5-phenyl-6-[(1R)-1-phenylethyl]sulfanylpyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.0340	uM
2-(3-methyloxetan-3-yl)-5-phenyl-6-(1-phenylethylsulfanyl)pyrazolo[3,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.0500	uM
2-(oxetan-3-ylmethyl)-5-phenyl-6-(1-phenylethylsulfanyl)pyrazolo[3,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.0600	uM
1-methyl-5-phenyl-6-(1-phenylethylsulfanyl)pyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.0730	uM
1-methyl-5-phenyl-6-(1-pyridin-2-ylethylsulfanyl)pyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.0890	uM
6-[(3-fluorophenyl)methylsulfanyl]-1-methyl-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.0900	uM
6-[1-(3-hydroxyphenyl)ethylsulfanyl]-1-methyl-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.0910	uM
1-methyl-5-phenyl-6-(1-pyridin-3-ylethylsulfanyl)pyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.0950	uM
2-(dimethylamino)-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1,3-thiazole-5-carboxamide	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2-piperazin-1-yl-1,3-thiazole-5-carboxamide	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
6-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
4-(3-fluorophenyl)-2-morpholin-4-yl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1,3-thiazole-5-carboxamide	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
4-(3-fluorophenyl)-2-(3-hydroxyazetidin-1-yl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1,3-thiazole-5-carboxamide	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1,3-thiazole-5-carboxamide	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
6-[2-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
4-(2-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1,3-thiazole-5-carboxamide	1923280: Inhibition of full length human ALDH1A3 using propionaldehyde as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins in presence of NAD by luminescence microplate reader analysis	ic50	0.1000	uM
1-methyl-5-phenyl-6-(1-pyrimidin-5-ylethylsulfanyl)pyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1000	uM
2-(oxetan-3-yl)-5-phenyl-6-(1-phenylethylsulfanyl)pyrazolo[3,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1090	uM
6-[1-(2-methoxyphenyl)ethylsulfanyl]-1-methyl-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1120	uM
1-methyl-5-phenyl-6-(1-phenylpropylsulfanyl)pyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1190	uM
6-[(3-fluorophenyl)methylsulfanyl]-2-(oxetan-3-yl)-5-phenylpyrazolo[3,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.1200	uM
methyl 4-(2-phenylimidazo[1,2-a]pyridin-8-yl)benzoate	1649842: Competitive inhibition of human recombinant ALDH1A3 pre-incubated for 5 mins before acetaldehyde addition by continuous spectrometric assay relative to control	ki	0.1200	uM
6-[1-(3-fluorophenyl)ethylsulfanyl]-1-methyl-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1280	uM
6-[(3-fluorophenyl)methylsulfanyl]-2-methyl-5-phenylpyrazolo[3,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.1300	uM
6-[(3-fluorophenyl)methylsulfanyl]-2-(oxetan-3-ylmethyl)-5-phenylpyrazolo[3,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.1300	uM
1-methyl-6-(2-methyl-1-phenylpropyl)sulfanyl-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1300	uM
6-[(3-fluorophenyl)methylsulfanyl]-1-methyl-5-phenylpyrazolo[4,5-c]pyridin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1400	uM
3-methyl-8,11-diphenyl-10-thia-3,4,8-triazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),4-triene-7,12-dione	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1500	uM
6-[(3-fluorophenyl)methylsulfanyl]-1-(oxetan-3-yl)-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.1700	uM
2-(cyclopropylmethyl)-6-[(3-fluorophenyl)methylsulfanyl]-5-phenylpyrazolo[3,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.1700	uM
13,14-dimethyl-8,12-dioxatetracyclo[7.7.0.02,6.011,15]hexadeca-1(9),2(6),10,13,15-pentaen-7-one	1441745: Inhibition of full length recombinant human ALDH1A3 expressed in Escherichia coli BL21(DE3) assessed as reduction in dehydrogenase activity by measuring NAD(P)H level preincubated for 2 mins followed by addition of propionaldehyde as substrate in presence of NAD+ by spectrophotometric method	ic50	0.1700	uM
6-[1-(3-methoxyphenyl)ethylsulfanyl]-1-methyl-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.1740	uM
6-[(3-fluorophenyl)methylsulfanyl]-1-methyl-5-(2-phenylethyl)pyrazolo[5,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.1800	uM
2,2-dichloro-N-[8-[(2,2-dichloroacetyl)amino]octyl]acetamide	1956428: Inhibition of human ALDH1A3 in presence of NAD+ by LC-MS/MS analysis	ic50	0.1870	uM
4-[1-methyl-4-oxo-6-(1-phenylethylsulfanyl)pyrazolo[5,4-d]pyrimidin-5-yl]benzonitrile	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.2000	uM
3-methyl-8,11-diphenyl-10-thia-3,4,8-triazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,12-tetraen-7-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.2400	uM
2-(oxetan-3-yl)-5-phenyl-6-(1-pyridin-3-ylethylsulfanyl)pyrazolo[3,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.2500	uM
4-propan-2-yloxybenzaldehyde	1826421: Inhibition of N-terminal-His6 tagged recombinant human ALDH1A3 assessed as reduction in NADH production using hexanal and NAD+ as substrate by fluorimetric analysis	ic50	0.2600	uM
3-nitro-4-pyrrolidin-1-ylbenzaldehyde	1826421: Inhibition of N-terminal-His6 tagged recombinant human ALDH1A3 assessed as reduction in NADH production using hexanal and NAD+ as substrate by fluorimetric analysis	ic50	0.2700	uM
2,3,5,6-tetramethylfuro[3,2-g]chromen-7-one	1441745: Inhibition of full length recombinant human ALDH1A3 expressed in Escherichia coli BL21(DE3) assessed as reduction in dehydrogenase activity by measuring NAD(P)H level preincubated for 2 mins followed by addition of propionaldehyde as substrate in presence of NAD+ by spectrophotometric method	ic50	0.2700	uM
3-methyl-4-piperidin-1-ylbenzaldehyde	1826421: Inhibition of N-terminal-His6 tagged recombinant human ALDH1A3 assessed as reduction in NADH production using hexanal and NAD+ as substrate by fluorimetric analysis	ic50	0.3000	uM
3-chloro-4-pyrrolidin-1-ylbenzaldehyde	1826421: Inhibition of N-terminal-His6 tagged recombinant human ALDH1A3 assessed as reduction in NADH production using hexanal and NAD+ as substrate by fluorimetric analysis	ic50	0.3100	uM
6-[(3-fluorophenyl)methylsulfanyl]-5-phenyl-1H-pyrazolo[5,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.3900	uM
2,3,5-trimethyl-6-propylfuro[3,2-g]chromen-7-one	1441745: Inhibition of full length recombinant human ALDH1A3 expressed in Escherichia coli BL21(DE3) assessed as reduction in dehydrogenase activity by measuring NAD(P)H level preincubated for 2 mins followed by addition of propionaldehyde as substrate in presence of NAD+ by spectrophotometric method	ic50	0.4000	uM
3-bromo-4-(dipropylamino)benzaldehyde	1826425: Competitive inhibition of N-terminal-His6 tagged recombinant human ALDH1A3 assessed as increase in Km without change in Vmax using hexanal as substrate by Michaelis-Menten analysis	ki	0.4600	uM
2-(oxetan-3-yl)-5-phenyl-6-(1-pyridin-2-ylethylsulfanyl)pyrazolo[3,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.4800	uM
2-[(3-fluorophenyl)methylsulfanyl]-3-phenylimidazo[5,1-f][1,2,4]triazin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.5000	uM
5-(4-ethynylphenyl)-1-methyl-6-(1-phenylethylsulfanyl)pyrazolo[5,4-d]pyrimidin-4-one	1752915: Inhibition of human ALDH1A3 assessed as NADH formation using propionaldehyde as substrate by spectrophotometery	ic50	0.5200	uM
2,6-diphenylimidazo[1,2-a]pyridine	1606577: Competitive inhibition of recombinant human 6His-tagged ALDH1A3 expressed in Escherichia coli BL21(DE3) using varying level of acetaldehyde as substrate preincubated for 5 mins followed by substrate addition by Michaelis-Menten plot analysis	ki	0.5400	uM
1-(cyclopropylmethyl)-6-[(3-fluorophenyl)methylsulfanyl]-5-phenylpyrazolo[5,4-d]pyrimidin-4-one	1387320: Inhibition of human recombinant ALDH1A3 assessed as reduction in of NAD(P)H formation incubated for 2 mins by spectrophotometry	ic50	0.5500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression, affects reaction	8
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases reaction	8
Tobacco Smoke Pollution	affects expression, increases expression	7
Particulate Matter	increases abundance, increases expression, affects cotreatment	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance	6
bisphenol A	increases expression, affects cotreatment, decreases expression	5
Estradiol	affects cotreatment, increases expression, decreases expression	5
Decitabine	affects expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
Arsenic Trioxide	affects binding, decreases reaction, decreases expression, increases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression, decreases expression	3
Arsenic	decreases expression, increases abundance, affects cotreatment	3
Cisplatin	increases reaction, affects expression, increases expression	3
Tretinoin	decreases expression, increases chemical synthesis	3
Valproic Acid	affects expression, increases expression	3
Aflatoxin B1	increases expression, increases methylation	3
bisphenol F	decreases expression, affects cotreatment, increases expression	2
sodium arsenate	decreases expression, increases abundance	2
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
bisphenol B	decreases expression, increases expression	2
bisphenol S	decreases expression, increases expression	2
bisphenol AF	increases expression, decreases expression	2
Resveratrol	decreases expression, affects cotreatment	2
Zoledronic Acid	increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Aerosols	increases expression	2

ChEMBL screening assays

55 unique, capped per target: 55 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3118128	Binding	Inhibition of human ALDH1A3 using propionaldehyde as substrate up to 100 uM preincubated for 1 min followed by substrate addition by spectrophotometric analysis	Selective ALDH3A1 inhibition by benzimidazole analogues increase mafosfamide sensitivity in cancer cells. — J Med Chem

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C6IK	U87MG/ALDH1A3-KO.1	Cancer cell line	Male
CVCL_C6J3	GSC-83/ALDH1A3-KO.1.2	Cancer cell line	Female
CVCL_C6J4	GSC-326/ALDH1A3-KO.1.1	Cancer cell line	Sex unspecified
CVCL_C6J5	GSC-326/ALDH1A3-KO.2.3	Cancer cell line	Sex unspecified
CVCL_C6J6	GSC-326/ALDH1A3-KO.2.4	Cancer cell line	Sex unspecified
CVCL_C6J7	GSC-326/ALDH1A3-KO.3.1	Cancer cell line	Sex unspecified
CVCL_C6J8	GSC-326/ALDH1A3-KO.3.4	Cancer cell line	Sex unspecified
CVCL_C6J9	GSC-326/ALDH1A3-KO.3.5	Cancer cell line	Sex unspecified

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms