ALDH1L1

Summary

ALDH1L1 (aldehyde dehydrogenase 1 family member L1, HGNC:3978) is a protein-coding gene on chromosome 3q21.3, encoding Cytosolic 10-formyltetrahydrofolate dehydrogenase (O75891). Cytosolic 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.

The protein encoded by this gene catalyzes the conversion of 10-formyltetrahydrofolate, nicotinamide adenine dinucleotide phosphate (NADP+), and water to tetrahydrofolate, NADPH, and carbon dioxide. The encoded protein belongs to the aldehyde dehydrogenase family. Loss of function or expression of this gene is associated with decreased apoptosis, increased cell motility, and cancer progression. There is an antisense transcript that overlaps on the opposite strand with this gene locus. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10840 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 151 total — 1 likely-pathogenic
• MANE Select transcript: NM_012190

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3978
Approved symbol	ALDH1L1
Name	aldehyde dehydrogenase 1 family member L1
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	10-fTHF, FDH
Ensembl gene	ENSG00000144908
Ensembl biotype	protein_coding
OMIM	600249
Entrez	10840

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 40 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000273450, ENST00000393431, ENST00000393434, ENST00000413612, ENST00000452905, ENST00000455064, ENST00000460368, ENST00000462808, ENST00000467370, ENST00000472186, ENST00000473607, ENST00000476245, ENST00000484724, ENST00000488356, ENST00000490367, ENST00000493803, ENST00000509952, ENST00000511283, ENST00000900777, ENST00000900778, ENST00000900779, ENST00000900780, ENST00000900781, ENST00000900782, ENST00000900783, ENST00000900784, ENST00000900785, ENST00000900786, ENST00000900787, ENST00000900788, ENST00000900789, ENST00000900790, ENST00000900791, ENST00000900792, ENST00000900793, ENST00000961075, ENST00000961076, ENST00000961077, ENST00000961078, ENST00000961079, ENST00000961080, ENST00000961081, ENST00000961082, ENST00000961083, ENST00000961084, ENST00000961085, ENST00000961086, ENST00000961087

RefSeq mRNA: 3 — MANE Select: NM_012190 NM_001270364, NM_001270365, NM_012190

CCDS: CCDS3034, CCDS58850, CCDS58851

Canonical transcript exons

ENST00000393434 — 23 exons

Exon	Start	End
ENSE00000000212	126103570	126103846
ENSE00002427214	126114557	126114656
ENSE00003467436	126155402	126155503
ENSE00003476046	126124364	126124451
ENSE00003477386	126112782	126112880
ENSE00003482803	126109944	126110109
ENSE00003491540	126105726	126105925
ENSE00003540129	126125616	126125721
ENSE00003557416	126146835	126146926
ENSE00003563156	126135535	126135662
ENSE00003615871	126131384	126131534
ENSE00003627703	126154554	126154643
ENSE00003628861	126130223	126130293
ENSE00003635032	126136764	126136883
ENSE00003635165	126153444	126153581
ENSE00003643733	126137813	126137960
ENSE00003645377	126118005	126118098
ENSE00003649788	126150406	126150531
ENSE00003685908	126107141	126107246
ENSE00003691807	126158405	126158639
ENSE00003733687	126157343	126157508
ENSE00003737062	126160853	126161002
ENSE00003903540	126180476	126180586

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 98.24.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3221 / max 242.1206, expressed in 335 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44319	2.1965	252
44318	1.3994	229
44320	0.2768	141
44321	0.1588	117
44324	0.1005	49
44323	0.0806	44
44322	0.0453	24
202913	0.0436	15
44325	0.0206	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.24	gold quality
liver	UBERON:0002107	96.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.50	gold quality
adult mammalian kidney	UBERON:0000082	96.00	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.72	gold quality
parotid gland	UBERON:0001831	95.68	gold quality
gastrocnemius	UBERON:0001388	95.08	gold quality
cranial nerve II	UBERON:0000941	95.05	gold quality
gluteal muscle	UBERON:0002000	94.36	gold quality
mucosa of stomach	UBERON:0001199	93.80	gold quality
muscle of leg	UBERON:0001383	93.78	gold quality
caudate nucleus	UBERON:0001873	93.10	gold quality
muscle organ	UBERON:0001630	92.53	gold quality
skeletal muscle organ	UBERON:0014892	92.53	gold quality
amygdala	UBERON:0001876	92.45	gold quality
body of pancreas	UBERON:0001150	92.43	gold quality
putamen	UBERON:0001874	92.38	gold quality
right ovary	UBERON:0002118	92.25	gold quality
left ovary	UBERON:0002119	92.17	gold quality
saliva-secreting gland	UBERON:0001044	92.12	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.06	gold quality
triceps brachii	UBERON:0001509	92.02	gold quality
nucleus accumbens	UBERON:0001882	91.87	gold quality
right adrenal gland cortex	UBERON:0035827	91.79	gold quality
left adrenal gland	UBERON:0001234	91.36	gold quality
right adrenal gland	UBERON:0001233	91.34	gold quality
nephron tubule	UBERON:0001231	91.32	gold quality
left adrenal gland cortex	UBERON:0035825	91.24	gold quality
minor salivary gland	UBERON:0001830	91.17	gold quality
kidney	UBERON:0002113	91.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.31
E-GEOD-84465	yes	11.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting ALDH1L1, 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-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-3166	98.24	66.63	1223

Literature-anchored findings (GeneRIF, showing 19)

• down-regulation of FDH in tumors is proposed to be one of the cellular mechanisms that enhance proliferation. (PMID:12065246)
• FDH antiproliferative effects on A549 cells include both G(1) cell cycle arrest and caspase-dependent apoptosis (PMID:12805405)
• None of the snps that defined 3 separate haplotype blocks in the FTHFD gene, rs2365004, rs11923466, rs2886059, rs10934751, rs2276731, rs1823213 and rs4646701 were associated with prostate cancer risk. (PMID:19064578)
• inhibition of cell motility by ALDH1L1 associated with dephosphorylation of the actin depolymerizing factor cofilin by PP1 and PP2A (PMID:20729910)
• Conserved catalytic residues of the ALDH1L1 aldehyde dehydrogenase domain control binding and discharging of the coenzyme. (PMID:21540484)
• The results in this study, for the first time, reveal that the mRNA and protein expressions of ALDH1L1 are significantly reduced in hepatocellular carcinoma tissues (PMID:21987076)
• one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. (PMID:24651765)
• ALDH1 is indicative of stemness and is a biomarker marker in colon cancer. (PMID:24953984)
• JNK1/2 phosphorylate Bid at Thr59 within the caspase cleavage site in response to ALDH1L1. (PMID:25077544)
• Data suggest that isoforms of FTHFD occur both in mitochondria and in cytosol; activity of cytosolic FTHFD appears to respond to supply of one-carbon groups in excess of those required for classical one-carbon metabolism. [REVIEW] (PMID:26567272)
• The polymorphic loci rs4646733, rs2305225, and rs2276731 in the ALDH1L1 gene maybe potential risk factors for neural tube defects in the Chinese population. (PMID:26993122)
• high transcription activities of ALDH1A2, ALDH1A3 and ALDH1L1 predicted worsen overall survival in gastric cancer patients (PMID:27015121)
• ALDH1L1 has a role in response to the combined treatment of gossypol and phenformin in non-small cell lung cancer (PMID:27384481)
• The three functional domains of ALDH1L1 was defined positions of the 4’-phosphopantetheine arm within the two catalytic domains and to predict N-terminal:intermediate and intermediate:C-terminal domain interfaces. (PMID:28414156)
• Our results suggest that ALDH1L1 may be a biomarker for predicting postoperative clinical outcomes. Moreover, ALDH1L1-rs2276724 and mRNA expression were associated with TP53 expression in HBV-related hepatocellular carcinoma patients (PMID:28714006)
• [Functional Hypermethylation of ALDH1L1, PLCL2, and PPP2R3A in Colon Cancer]. (PMID:32392189)
• Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children. (PMID:35460232)
• Abnormal downregulation of 10-formyltetrahydrofolate dehydrogenase promotes the progression of oral squamous cell carcinoma by activating PI3K/Akt/Rb pathway. (PMID:36336972)
• One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression. (PMID:37596270)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	aldh1l1	ENSDARG00000077004
mus_musculus	Aldh1l1	ENSMUSG00000030088
rattus_norvegicus	Aldh1l1	ENSRNOG00000047023
drosophila_melanogaster	CG8665	FBGN0032945
drosophila_melanogaster	CG31075	FBGN0051075
caenorhabditis_elegans		WBGENE00000107
caenorhabditis_elegans		WBGENE00000108
caenorhabditis_elegans		WBGENE00000109

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), ALDH4A1 (ENSG00000159423), ALDH16A1 (ENSG00000161618), ALDH7A1 (ENSG00000164904), ALDH1A1 (ENSG00000165092), ALDH1A3 (ENSG00000184254)

Protein

Protein identifiers

Cytosolic 10-formyltetrahydrofolate dehydrogenase — O75891 (reviewed: O75891)

Alternative names: Aldehyde dehydrogenase family 1 member L1

All UniProt accessions (8): O75891, A0A0S2Z586, C9IZ36, C9JY00, C9JYZ6, D6RFJ7, F2Z324, F8WC34

UniProt curated annotations — full annotation on UniProt →

Function. Cytosolic 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide. May also have an NADP(+)-dependent aldehyde dehydrogenase activity towards formaldehyde, acetaldehyde, propionaldehyde, and benzaldehyde.

Subunit / interactions. Homotetramer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Highly expressed in liver, pancreas and kidney.

Post-translational modifications. Phosphopantetheinylation at Ser-354 by AASDHPPT is required for the formyltetrahydrofolate dehydrogenase activity.

Domain organisation. The N-terminal hydrolase domain has an NADP-independent formyltetrahydrofolate hydrolase activity, releasing formate and tetrahydrofolate. The C-terminal aldehyde dehydrogenase domain has an NADP-dependent dehydrogenase activity. It catalyzes the oxidation of formate, released by the hydrolysis of formyltetrahydrofolate, into CO2. The carrier domain is phosphopantetheinylated and uses the 4’-phosphopantetheine/4’-PP swinging arm to transfer the formyl group released by the N-terminal formyltetrahydrofolate hydrolase activity to the C-terminal aldehyde dehydrogenase domain that catalyzes its NADP-dependent oxidation into CO2. The overall NADP-dependent physiological reaction requires the 3 domains (N-terminal hydrolase, C-terminal aldehyde dehydrogenase and carrier domains) to convert formyltetrahydrofolate into tetrahydrofolate and CO2.

Similarity. In the N-terminal section; belongs to the GART family. In the C-terminal section; belongs to the aldehyde dehydrogenase family. ALDH1L subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
O75891-1	1	yes
O75891-2	2
O75891-3	3
O75891-4	4

RefSeq proteins (3): NP_001257293, NP_001257294, NP_036322* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001555	GART_AS	Active_site
IPR002376	Formyl_transf_N	Domain
IPR005793	Formyl_trans_C	Domain
IPR009081	PP-bd_ACP	Domain
IPR011034	Formyl_transferase-like_C_sf	Homologous_superfamily
IPR011407	10_FTHF_DH	Family
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
IPR036477	Formyl_transf_N_sf	Homologous_superfamily
IPR036736	ACP-like_sf	Homologous_superfamily
IPR037022	Formyl_trans_C_sf	Homologous_superfamily

Pfam: PF00171, PF00550, PF00551, PF02911

Enzyme classification (BRENDA):

• EC 1.5.1.6 — formyltetrahydrofolate dehydrogenase (BRENDA: 7 organisms, 92 substrates, 25 inhibitors, 22 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
10-FORMYLTETRAHYDROFOLATE	0.0044–0.05	13
NADP+	0.0004–0.0035	7
10-FORMYL-5,8-DIDEAZAFOLATE	0.0032	1
10-FORMYLTETRAHYDROPTEROYLPENTAGLUTAMATE	—	0

Catalyzed reactions (Rhea), 1 shown:

• (6R)-10-formyltetrahydrofolate + NADP(+) + H2O = (6S)-5,6,7,8-tetrahydrofolate + CO2 + NADPH + H(+) (RHEA:10180)

UniProt features (84 total): strand 16, helix 15, sequence variant 10, binding site 9, modified residue 9, sequence conflict 9, splice variant 4, active site 3, turn 3, region of interest 2, chain 1, domain 1, site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2BW0	X-RAY DIFFRACTION	1.7
2CFI	X-RAY DIFFRACTION	1.85
7YJJ	ELECTRON MICROSCOPY	6.31
2CQ8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75891-F1	94.18	0.83

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 (4): 142 (essential for catalytic activity); 106 (proton donor); 673 (proton acceptor); 707 (proton donor)

Ligand- & substrate-binding residues (9): 597–600; 630–635; 650–651; 673–674; 757; 804–806; 88–90; 142; 571–573

Post-translational modifications (9): 9, 38, 354, 629, 631, 660, 767, 825, 882

Mutagenesis-validated functional residues (1):

Position	Phenotype
354	loss of phosphopantetheinylation by aasdhppt. loss of formyltetrahydrofolate dehydrogenase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines
R-HSA-1430728	Metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors

MSigDB gene sets: 159 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, MODULE_93, GNF2_GSTM1, GOBP_NADPPLUS_METABOLIC_PROCESS, GNF2_HPN, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, KEGG_ONE_CARBON_POOL_BY_FOLATE, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, BOYAULT_LIVER_CANCER_SUBCLASS_G12_DN, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN

GO Biological Process (5): NADPH regeneration (GO:0006740), 10-formyltetrahydrofolate catabolic process (GO:0009258), tetrahydrofolate interconversion (GO:0035999), one-carbon metabolic process (GO:0006730), biosynthetic process (GO:0009058)

GO Molecular Function (6): aldehyde dehydrogenase (NAD+) activity (GO:0004029), formyltetrahydrofolate dehydrogenase activity (GO:0016155), catalytic activity (GO:0003824), protein binding (GO:0005515), 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 (4): mitochondrion (GO:0005739), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
generation of precursor metabolites and energy	1
NADP+ metabolic process	1
10-formyltetrahydrofolate metabolic process	1
folic acid-containing compound catabolic process	1
dicarboxylic acid catabolic process	1
one-carbon metabolic process	1
tetrahydrofolate metabolic process	1
small molecule metabolic process	1
metabolic process	1
aldehyde dehydrogenase [NAD(P)+] activity	1
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	1
molecular_function	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	1
intracellular membrane-bounded organelle	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALDH1L1	GART	P22102	826
ALDH1L1	GFAP	P14136	753
ALDH1L1	SLC1A3	P43003	751
ALDH1L1	SLC1A2	P43004	713
ALDH1L1	S100B	P04271	697
ALDH1L1	OLIG2	Q13516	636
ALDH1L1	MTHFD1	P11586	621
ALDH1L1	GLUL	P15104	613
ALDH1L1	RBFOX3	A6NFN3	593
ALDH1L1	AIF1	P55008	590
ALDH1L1	ALDH18A1	P54886	545
ALDH1L1	MTHFD1L	Q6UB35	534
ALDH1L1	GJB6	O95452	533
ALDH1L1	HEPACAM	Q14CZ8	532
ALDH1L1	SHMT1	P34896	530

IntAct

158 interactions, top by confidence:

A	B	Type	Score
NDUFAF4	NDUFS7	psi-mi:“MI:0914”(association)	0.790
NDUFAF5	NDUFAF8	psi-mi:“MI:0914”(association)	0.750
LYRM2	NDUFAB1	psi-mi:“MI:0914”(association)	0.730
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
COQ8A	COQ9	psi-mi:“MI:0914”(association)	0.670
FAM90A1	KPNA3	psi-mi:“MI:0914”(association)	0.670
SDHAF3	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
ETFRF1	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
LYRM7	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
ALDH1L1	ALDH1L2	psi-mi:“MI:0915”(physical association)	0.590
COQ5	COQ9	psi-mi:“MI:0914”(association)	0.590
DCAF7	PFDN6	psi-mi:“MI:0914”(association)	0.570
APOOL	MTX2	psi-mi:“MI:0914”(association)	0.530
SLC2A5	RBFOX3	psi-mi:“MI:0914”(association)	0.530
COQ3	COQ9	psi-mi:“MI:0914”(association)	0.500
COQ4	COQ9	psi-mi:“MI:0914”(association)	0.500
PB2	ALDH1L1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (48): ALDH1L2 (Affinity Capture-MS), ALDH1L1 (Affinity Capture-MS), ALDH1L1 (Proximity Label-MS), ALDH1L1 (Affinity Capture-MS), ALDH1L1 (Biochemical Activity), HSP90B1 (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), USP9X (Affinity Capture-MS), USP11 (Affinity Capture-MS), USP47 (Affinity Capture-MS), PSMC4 (Affinity Capture-MS), PSMD14 (Affinity Capture-MS), PSMC2 (Affinity Capture-MS), PSMC3 (Affinity Capture-MS), PSMD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E3T3B5, A0A0E3T552, A0A162J448, A0A5C1REZ4, A0A6J4B898, B3VMC0, B6ECN9, B8M9K4, C0P9J6, C6KEM4, E1V7V8, G5DDC2, H1ZV37, H8ZPX2, O04895, O06837, O24174, O75891, P0DXC6, P17202, P28037, P28237, P42757, P43503, P52476, P81406, P93338, Q1ERI2, Q1JUP4, Q1WIQ6, Q3SY69, Q40024, Q43272, Q56R04, Q5RFM9, Q66HF8, Q79EM7, Q84LK3, Q8K009, Q8LK61

Diamond homologs: A0A2I7G3B0, A0B2F6, A1UVS4, A2RWD6, A3M365, A3MEC6, A3NKP8, A3P6B0, A4JJG5, A4XPI6, A6VEI4, A6ZR27, A8GBX8, A9AN00, B0V944, B0VST2, B1K708, B1Z033, B2HV80, B2JS88, B2TCJ9, B4EHJ1, B7GYG4, B7I896, C5I9X1, C7A2A0, O14293, O34660, O35945, O74187, O75891, O93344, O94788, P00352, P05091, P08157, P11884, P12762, P13601, P15437

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex I biogenesis	10	19.7×	3e-09
Mitochondrial protein import	9	18.0×	6e-08
Respiratory electron transport	15	17.0×	7e-13
Aerobic respiration and respiratory electron transport	14	14.8×	3e-11
Mitochondrial biogenesis	6	12.0×	2e-04
Mitochondrial protein degradation	7	9.5×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
ubiquinone biosynthetic process	9	80.2×	2e-13
mitochondrial respiratory chain complex I assembly	8	31.3×	3e-08
mitochondrial electron transport, NADH to ubiquinone	6	20.5×	6e-05
proton motive force-driven mitochondrial ATP synthesis	6	15.1×	2e-04
aerobic respiration	5	11.8×	2e-03
mitochondrion organization	8	11.6×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	109
Likely benign	5
Benign	11

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
625698	GRCh37/hg19 3q21.2-21.3(chr3:124369671-126423192)	Likely pathogenic

SpliceAI

4768 predictions. Top by Δscore:

Variant	Effect	Δscore
3:126105720:GGTTA:G	donor_loss	1.0000
3:126105721:GTTAC:G	donor_loss	1.0000
3:126105722:TTACC:T	donor_loss	1.0000
3:126105724:A:AC	donor_gain	1.0000
3:126105725:C:CC	donor_gain	1.0000
3:126105725:C:CT	donor_loss	1.0000
3:126105728:AGAT:A	donor_gain	1.0000
3:126105729:G:C	donor_gain	1.0000
3:126105923:TCC:T	acceptor_gain	1.0000
3:126105924:CC:C	acceptor_gain	1.0000
3:126105924:CCC:C	acceptor_gain	1.0000
3:126105925:CC:C	acceptor_gain	1.0000
3:126105926:C:CC	acceptor_gain	1.0000
3:126107139:AC:A	donor_gain	1.0000
3:126107140:CC:C	donor_gain	1.0000
3:126107140:CCCAT:C	donor_gain	1.0000
3:126109939:CTCA:C	donor_loss	1.0000
3:126109940:TCA:T	donor_loss	1.0000
3:126109941:CACC:C	donor_loss	1.0000
3:126109942:A:C	donor_loss	1.0000
3:126109943:C:CT	donor_loss	1.0000
3:126109943:CCTGG:C	donor_gain	1.0000
3:126109988:T:TA	donor_gain	1.0000
3:126112775:GACTT:G	donor_loss	1.0000
3:126112776:ACTTA:A	donor_loss	1.0000
3:126112777:CTTAC:C	donor_loss	1.0000
3:126112779:TAC:T	donor_loss	1.0000
3:126112779:TACC:T	donor_gain	1.0000
3:126112780:A:AC	donor_gain	1.0000
3:126112780:ACCA:A	donor_gain	1.0000

AlphaMissense

5922 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:126105743:C:T	G879E	1.000
3:126105763:G:C	F872L	1.000
3:126105763:G:T	F872L	1.000
3:126105765:A:G	F872L	1.000
3:126125672:A:G	W582R	1.000
3:126125672:A:T	W582R	1.000
3:126125694:G:C	N574K	1.000
3:126125694:G:T	N574K	1.000
3:126103846:C:A	G885V	0.999
3:126105726:C:G	G885R	0.999
3:126105726:C:T	G885R	0.999
3:126105728:A:G	L884P	0.999
3:126105746:G:A	S878F	0.999
3:126105758:C:T	G874E	0.999
3:126105761:C:T	G873E	0.999
3:126105802:A:C	F859L	0.999
3:126105802:A:T	F859L	0.999
3:126105804:A:G	F859L	0.999
3:126105878:A:G	L834P	0.999
3:126105878:A:T	L834Q	0.999
3:126107176:G:C	F806L	0.999
3:126107176:G:T	F806L	0.999
3:126107178:A:G	F806L	0.999
3:126112842:G:C	C707W	0.999
3:126112843:C:T	C707Y	0.999
3:126112844:A:G	C707R	0.999
3:126112845:A:C	N706K	0.999
3:126112845:A:T	N706K	0.999
3:126112852:C:A	G704V	0.999
3:126114618:A:G	L674P	0.999

dbSNP variants (sampled 300 via entrez): RS1000006942 (3:126112373 C>G,T), RS1000032308 (3:126140806 G>A), RS1000041908 (3:126190739 G>A), RS1000050284 (3:126196892 G>A,C), RS1000104090 (3:126178047 A>G), RS1000132385 (3:126190149 C>G,T), RS1000136323 (3:126191092 A>G), RS1000181906 (3:126194294 C>T), RS1000220539 (3:126161899 G>A), RS1000242924 (3:126150989 T>A), RS1000301706 (3:126156238 T>C), RS1000309958 (3:126127856 C>A,T), RS1000328772 (3:126156426 C>T), RS1000354948 (3:126179226 G>A), RS1000363017 (3:126138220 A>C)

Disease associations

OMIM: gene MIM:600249 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): chromosome 16 trisomy (MONDO:0022180)

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001852_4	Metabolite levels	2.000000e-06
GCST002391_4	Plasma homocysteine levels (post-methionine load test)	7.000000e-13
GCST004171_4	Macular telangiectasia type 2	2.000000e-07
GCST006661_116	Male-pattern baldness	1.000000e-16
GCST007836_4	Glycine levels	2.000000e-28
GCST007837_3	Glycine levels	2.000000e-09
GCST007838_3	Glycine levels	2.000000e-22
GCST008151_27	Waist circumference	3.000000e-06
GCST008160_72	Waist circumference	3.000000e-06
GCST009240_433	Serum metabolite levels (CMS)	8.000000e-14
GCST009242_401	Serum metabolite levels	2.000000e-09
GCST009597_113	Multiple sclerosis	2.000000e-07
GCST90002390_156	Mean corpuscular hemoglobin	2.000000e-09
GCST90002392_302	Mean corpuscular volume	1.000000e-09
GCST90013405_69	Liver enzyme levels (alanine transaminase)	5.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0004578	homocysteine measurement
EFO:1002009	macular telangiectasia type 2
EFO:0009767	glycine measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2886059	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2886059	ALDH1L1	3	0.00	1	methylphenidate

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression, decreases expression	5
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
bisphenol A	affects expression, decreases expression	2
bisphenol S	increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
propionaldehyde	decreases expression	1
5-methyltetrahydrofolate	decreases abundance	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	increases reaction, affects binding	1
nutlin 3	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation	1
Azathioprine	increases expression	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Folic Acid	increases degradation	1
Indomethacin	affects cotreatment, increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1

Clinical trials (associated diseases)

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