ALDH1L2

Summary

ALDH1L2 (aldehyde dehydrogenase 1 family member L2, HGNC:26777) is a protein-coding gene on chromosome 12q23.3, encoding Mitochondrial 10-formyltetrahydrofolate dehydrogenase (Q3SY69). Mitochondrial 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.

This gene encodes a member of both the aldehyde dehydrogenase superfamily and the formyl transferase superfamily. This member is the mitochondrial form of 10-formyltetrahydrofolate dehydrogenase (FDH), which converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in an NADP(+)-dependent reaction, and plays an essential role in the distribution of one-carbon groups between the cytosolic and mitochondrial compartments of the cell. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 160428 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 99 total — 1 pathogenic
• MANE Select transcript: NM_001034173

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26777
Approved symbol	ALDH1L2
Name	aldehyde dehydrogenase 1 family member L2
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ38508, mtFDH
Ensembl gene	ENSG00000136010
Ensembl biotype	protein_coding
OMIM	613584
Entrez	160428

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000258494, ENST00000548418, ENST00000549335, ENST00000550088, ENST00000552270, ENST00000552427, ENST00000652515, ENST00000890519, ENST00000890520

RefSeq mRNA: 1 — MANE Select: NM_001034173 NM_001034173

CCDS: CCDS31891

Canonical transcript exons

ENST00000258494 — 23 exons

Exon	Start	End
ENSE00001132855	105066568	105066669
ENSE00001165885	105068719	105068884
ENSE00001193418	105070570	105070804
ENSE00002399118	105084389	105084458
ENSE00003465929	105038103	105038202
ENSE00003467137	105052812	105052931
ENSE00003467695	105061627	105061752
ENSE00003495802	105046710	105046815
ENSE00003500033	105046899	105046969
ENSE00003524134	105060981	105061072
ENSE00003526901	105026545	105026744
ENSE00003546477	105062888	105063022
ENSE00003549417	105073861	105074005
ENSE00003566583	105065267	105065356
ENSE00003568853	105019790	105024479
ENSE00003590463	105052090	105052217
ENSE00003600608	105049908	105050058
ENSE00003608418	105030324	105030429
ENSE00003629174	105034300	105034398
ENSE00003631193	105031769	105031934
ENSE00003634180	105058073	105058220
ENSE00003658284	105039713	105039806
ENSE00003694554	105040607	105040694

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 92.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2472 / max 221.5980, expressed in 1200 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133024	6.4014	1000
133027	2.6765	877
133026	1.2546	545
133028	0.4020	239
133025	0.3483	217
133022	0.1644	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	92.86	gold quality
body of pancreas	UBERON:0001150	91.16	gold quality
stromal cell of endometrium	CL:0002255	89.57	gold quality
epithelial cell of pancreas	CL:0000083	89.49	gold quality
pancreas	UBERON:0001264	87.26	gold quality
parotid gland	UBERON:0001831	83.23	gold quality
calcaneal tendon	UBERON:0003701	82.67	gold quality
tendon	UBERON:0000043	82.34	gold quality
tendon of biceps brachii	UBERON:0008188	81.17	gold quality
islet of Langerhans	UBERON:0000006	80.19	gold quality
bone marrow cell	CL:0002092	80.05	gold quality
descending thoracic aorta	UBERON:0002345	78.62	gold quality
ascending aorta	UBERON:0001496	78.57	gold quality
thoracic aorta	UBERON:0001515	78.55	gold quality
right coronary artery	UBERON:0001625	78.27	gold quality
left coronary artery	UBERON:0001626	77.53	gold quality
ganglionic eminence	UBERON:0004023	76.91	gold quality
coronary artery	UBERON:0001621	76.79	gold quality
aorta	UBERON:0000947	76.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.60	gold quality
cortical plate	UBERON:0005343	75.87	gold quality
saliva-secreting gland	UBERON:0001044	75.83	gold quality
smooth muscle tissue	UBERON:0001135	75.81	gold quality
visceral pleura	UBERON:0002401	75.67	gold quality
popliteal artery	UBERON:0002250	75.57	gold quality
tibial artery	UBERON:0007610	75.54	gold quality
trachea	UBERON:0003126	75.51	gold quality
ventricular zone	UBERON:0003053	75.34	gold quality
synovial joint	UBERON:0002217	75.29	gold quality
right hemisphere of cerebellum	UBERON:0014890	75.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.64
E-GEOD-124858	no	508.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

220 targeting ALDH1L2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3173-3P	99.98	66.49	1217

Literature-anchored findings (GeneRIF, showing 6)

• Our study identifies human PPT as the FDH-modifying enzyme and supports the hypothesis that mammals utilize a single enzyme for all phosphopantetheinylation reactions. (PMID:19933275)
• a gene at chromosome locus 12q24.11 of the human genome, the product of which has 74% sequence similarity with cytosolic FDH (PMID:20498374)
• ALDH1L2 has enzymatic properties similar to its cytosolic counterpart (PMID:21238436)
• ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis. (PMID:37245210)
• Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder. (PMID:38193334)
• FOXO1 induced fatty acid oxidation in hepatic cells by targeting ALDH1L2. (PMID:38923573)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	aldh1l2	ENSDARG00000070230
mus_musculus	Aldh1l2	ENSMUSG00000020256
rattus_norvegicus	Aldh1l2	ENSRNOG00000008586
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), ALDH1B1 (ENSG00000137124), ALDH9A1 (ENSG00000143149), ALDH1L1 (ENSG00000144908), ALDH4A1 (ENSG00000159423), ALDH16A1 (ENSG00000161618), ALDH7A1 (ENSG00000164904), ALDH1A1 (ENSG00000165092), ALDH1A3 (ENSG00000184254)

Protein

Protein identifiers

Mitochondrial 10-formyltetrahydrofolate dehydrogenase — Q3SY69 (reviewed: Q3SY69)

Alternative names: Aldehyde dehydrogenase family 1 member L2

All UniProt accessions (3): A0A494C1M4, Q3SY69, H0YHN9

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in pancreas, heart, brain and skeletal muscle.

Post-translational modifications. Phosphopantetheinylation at Ser-375 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 (3)

UniProt ID	Names	Canonical?
Q3SY69-1	1	yes
Q3SY69-2	2
Q3SY69-3	3

RefSeq proteins (1): NP_001029345* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001555	GART_AS	Active_site
IPR002376	Formyl_transf_N	Domain
IPR005793	Formyl_trans_C	Domain
IPR006162	Ppantetheine_attach_site	PTM
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 (33 total): binding site 9, modified residue 7, splice variant 4, active site 3, region of interest 2, mutagenesis site 2, chain 1, transit peptide 1, site 1, domain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3SY69-F1	92.71	0.81

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): 164 (essential for catalytic activity); 128 (proton donor); 694 (proton acceptor); 728 (proton donor)

Ligand- & substrate-binding residues (9): 592–594; 618–621; 651–656; 671–672; 694–695; 778; 825–827; 110–112; 164

Post-translational modifications (7): 31, 60, 375, 650, 681, 788, 903

Mutagenesis-validated functional residues (2):

Position	Phenotype
374	no effect on phosphopantetheinylation.
375	loss of phosphopantetheinylation.

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: 146 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_NADPPLUS_METABOLIC_PROCESS, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GROSS_HYPOXIA_VIA_ELK3_DN, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_TETRAHYDROFOLATE_METABOLIC_PROCESS, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP

GO Biological Process (6): fatty acid beta-oxidation (GO:0006635), one-carbon metabolic process (GO:0006730), NADPH regeneration (GO:0006740), 10-formyltetrahydrofolate catabolic process (GO:0009258), folic acid metabolic process (GO:0046655), 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 (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), 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
cellular anatomical structure	2
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
small molecule metabolic process	1
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
folic acid-containing compound metabolic process	1
dicarboxylic acid 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
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALDH1L2	MTHFD2	P13995	701
ALDH1L2	MTHFD1	P11586	695
ALDH1L2	SHMT1	P34896	683
ALDH1L2	MTHFD1L	Q6UB35	664
ALDH1L2	SHMT2	P34897	635
ALDH1L2	MTHFD2L	Q9H903	635
ALDH1L2	ALDH18A1	P54886	626
ALDH1L2	GLDC	P23378	556
ALDH1L2	DMGDH	Q9UI17	532
ALDH1L2	DHFR	P00374	520
ALDH1L2	DHFR2	Q86XF0	461
ALDH1L2	MTHFR	P42898	459
ALDH1L2	PSAT1	Q9Y617	446
ALDH1L2	ATIC	P31939	444
ALDH1L2	MTR	Q99707	414

IntAct

49 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SFXN5	CTSA	psi-mi:“MI:0914”(association)	0.640
ALDH1L1	ALDH1L2	psi-mi:“MI:0915”(physical association)	0.590
HTT	ALDH1L2	psi-mi:“MI:0915”(physical association)	0.560
ALDH1L2	WDR11	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
ALDH1L2	PTX3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
CHD8	BLTP3B	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAIP1	TIMM44	psi-mi:“MI:0914”(association)	0.350
TUBGCP4	SPTLC1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
F	TES	psi-mi:“MI:0914”(association)	0.350
ODF2	ELAPOR2	psi-mi:“MI:0914”(association)	0.350
SLC25A16	TOMM70	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
C1QA	VWA8	psi-mi:“MI:0914”(association)	0.350
C1QC	VWA8	psi-mi:“MI:0914”(association)	0.350
C1QTNF9B	DNASE2	psi-mi:“MI:0914”(association)	0.350
EMID1	NDUFS4	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): ALDH1L2 (Affinity Capture-MS), ALDH1L2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), TTC5 (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), SUGT1 (Affinity Capture-MS), WDR11 (Affinity Capture-MS), POLA1 (Affinity Capture-MS), VWA9 (Affinity Capture-MS), ALDH1L2 (Affinity Capture-MS), SUGT1 (Affinity Capture-MS), ALDH1L2 (Affinity Capture-MS), WDR11 (Affinity Capture-MS), ALDH1L2 (Affinity Capture-RNA), ALDH1L2 (Affinity Capture-MS)

ESM2 similar proteins: A0A023I4F1, A0A024SMV2, A0A1V6PAN1, A0A3Q9U4Z5, A0A7L9EZZ4, A0A8F4S717, A2Q8B5, B6H062, B8N8Q9, B8NI24, C5FFQ7, G3XMB9, G4MVZ3, G4MZI3, I1RV17, O14075, O42633, O42888, O59711, P00908, P00931, P05328, P06531, P0CU82, P18483, P24773, P25170, P27800, P38999, P53839, P9WEY3, Q04869, Q0CS91, Q0CSA3, Q0GYU4, Q0GYU5, Q0UK52, Q10494, Q2HEW4, Q3SY69

Diamond homologs: A0A162J448, A0A2I7G3B0, A0A5C1REZ4, A3M365, A4TNP1, A4XPI6, A5VPA5, A5WA96, A6VEI4, A6X2G8, A6ZR27, A7FKL5, A7N2Q0, A7ZI51, A7ZWV5, A9M9H7, B0CKN3, B0KN18, B0RNV0, B0V944, B1J0W5, B1J2K9, B1JSQ9, B1XET7, B2FQ90, B2HV80, B2K8U5, B2SA42, B3PTE1, B4SHW0, B5Y007, B5Z1R1, B5ZUG3, B6I075, B7GYG4, B7I896, B7L441, B7M2V6, B7N8L4, B7NK50

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	76
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1340640	GRCh37/hg19 12q23.3-24.12(chr12:104230462-111984801)x1	Pathogenic

SpliceAI

3609 predictions. Top by Δscore:

Variant	Effect	Δscore
12:105024405:T:A	donor_gain	1.0000
12:105026744:CCTG:C	acceptor_gain	1.0000
12:105030317:AACCT:A	donor_loss	1.0000
12:105030318:ACCT:A	donor_loss	1.0000
12:105030319:CCT:C	donor_loss	1.0000
12:105030320:CTA:C	donor_loss	1.0000
12:105030322:A:AC	donor_gain	1.0000
12:105030322:AC:A	donor_gain	1.0000
12:105030323:C:CA	donor_loss	1.0000
12:105030323:C:CC	donor_gain	1.0000
12:105030323:CC:C	donor_gain	1.0000
12:105030366:T:TA	donor_gain	1.0000
12:105030425:AAAGC:A	acceptor_gain	1.0000
12:105030427:AGC:A	acceptor_gain	1.0000
12:105030427:AGCC:A	acceptor_loss	1.0000
12:105030428:GC:G	acceptor_gain	1.0000
12:105030429:CCTT:C	acceptor_gain	1.0000
12:105030430:C:CC	acceptor_gain	1.0000
12:105030430:C:T	acceptor_gain	1.0000
12:105030431:T:C	acceptor_gain	1.0000
12:105030434:T:C	acceptor_gain	1.0000
12:105030434:T:TC	acceptor_gain	1.0000
12:105034299:CCA:C	donor_gain	1.0000
12:105034299:CCACT:C	donor_gain	1.0000
12:105038198:CACAG:C	acceptor_gain	1.0000
12:105038200:CAG:C	acceptor_gain	1.0000
12:105038203:C:CC	acceptor_gain	1.0000
12:105039707:CAATA:C	donor_loss	1.0000
12:105039708:AATAC:A	donor_loss	1.0000
12:105039709:ATACC:A	donor_loss	1.0000

AlphaMissense

6061 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:105026582:A:C	F893L	1.000
12:105026582:A:T	F893L	1.000
12:105026584:A:G	F893L	1.000
12:105039746:C:T	G671E	1.000
12:105039752:A:G	F669S	1.000
12:105046766:A:G	W603R	1.000
12:105046766:A:T	W603R	1.000
12:105046788:G:C	N595K	1.000
12:105046788:G:T	N595K	1.000
12:105046791:C:A	W594C	1.000
12:105046791:C:G	W594C	1.000
12:105046793:A:G	W594R	1.000
12:105046793:A:T	W594R	1.000
12:105024479:C:A	G906V	0.999
12:105026550:T:G	D904A	0.999
12:105026556:C:T	G902E	0.999
12:105026562:C:T	G900D	0.999
12:105026577:C:T	G895E	0.999
12:105026580:C:T	G894D	0.999
12:105026697:A:G	L855S	0.999
12:105030359:A:C	F827L	0.999
12:105030359:A:T	F827L	0.999
12:105030361:A:G	F827L	0.999
12:105034363:G:C	N727K	0.999
12:105034363:G:T	N727K	0.999
12:105034375:G:C	N723K	0.999
12:105034375:G:T	N723K	0.999
12:105038164:A:G	L695P	0.999
12:105038166:C:A	E694D	0.999
12:105038166:C:G	E694D	0.999

dbSNP variants (sampled 300 via entrez): RS1000138470 (12:105023349 C>G,T), RS1000176813 (12:105083719 T>A,C), RS1000178141 (12:105072028 G>A), RS1000226014 (12:105044949 G>A,T), RS1000247947 (12:105076676 A>G), RS1000272419 (12:105032627 C>A), RS1000292180 (12:105051238 A>G), RS1000358544 (12:105082897 A>G,T), RS1000403979 (12:105058897 T>C), RS1000409789 (12:105038386 A>T), RS1000412753 (12:105039996 G>T), RS1000512339 (12:105063297 A>T), RS1000515457 (12:105019477 G>C), RS1000619289 (12:105026438 C>T), RS1000664126 (12:105050908 C>G)

Disease associations

OMIM: gene MIM:613584 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal recessive
leukodystrophy	Limited	Autosomal recessive

Mondo (3): neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038), leukodystrophy (MONDO:0019046)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010566_8	Benign childhood epilepsy with centro-temporal spikes	9.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
bisphenol A	increases expression, decreases expression	3
Cyclosporine	increases expression	3
perfluorooctanoic acid	increases expression	2
didecyldimethylammonium	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
tungsten carbide	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
alpha phellandrene	increases expression	1
10-formyltetrahydropteroylglutamic acid	increases metabolic processing	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
trichostatin A	increases expression	1
arsenite	affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
5,6,7,8-tetrahydrofolic acid	increases chemical synthesis	1
hydroquinone	increases expression	1
isobutyl alcohol	increases expression, affects cotreatment, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit