ALAS1

Summary

ALAS1 (5’-aminolevulinate synthase 1, HGNC:396) is a protein-coding gene on chromosome 3p21.2, encoding 5-aminolevulinate synthase, non-specific, mitochondrial (P13196). Catalyzes the pyridoxal 5’-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products.

This gene encodes the mitochondrial enzyme which is catalyzes the rate-limiting step in heme (iron-protoporphyrin) biosynthesis. The enzyme encoded by this gene is the housekeeping enzyme; a separate gene encodes a form of the enzyme that is specific for erythroid tissue. The level of the mature encoded protein is regulated by heme: high levels of heme down-regulate the mature enzyme in mitochondria while low heme levels up-regulate. A pseudogene of this gene is located on chromosome 12. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 211 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 90 total — 2 pathogenic
• MANE Select transcript: NM_000688

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:396
Approved symbol	ALAS1
Name	5’-aminolevulinate synthase 1
Location	3p21.2
Locus type	gene with protein product
Status	Approved
Aliases	ALAS-H
Ensembl gene	ENSG00000023330
Ensembl biotype	protein_coding
OMIM	125290
Entrez	211

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 37 protein_coding

ENST00000310271, ENST00000394965, ENST00000459884, ENST00000469224, ENST00000484952, ENST00000493402, ENST00000864926, ENST00000864927, ENST00000864928, ENST00000864929, ENST00000864930, ENST00000864931, ENST00000864932, ENST00000864933, ENST00000864934, ENST00000864935, ENST00000864936, ENST00000864937, ENST00000864938, ENST00000864939, ENST00000864940, ENST00000864941, ENST00000864942, ENST00000864943, ENST00000864944, ENST00000864945, ENST00000930956, ENST00000942092, ENST00000942093, ENST00000942094, ENST00000942095, ENST00000942096, ENST00000942097, ENST00000942098, ENST00000942099, ENST00000942100, ENST00000942101

RefSeq mRNA: 4 — MANE Select: NM_000688 NM_000688, NM_001304443, NM_001304444, NM_199166

CCDS: CCDS2847

Canonical transcript exons

ENST00000484952 — 12 exons

Exon	Start	End
ENSE00001905437	52198160	52198255
ENSE00002225411	52202507	52202734
ENSE00002267562	52198672	52198848
ENSE00002310805	52199210	52199440
ENSE00002326932	52214020	52214327
ENSE00002337868	52204693	52204915
ENSE00002340507	52212258	52212420
ENSE00002350698	52206572	52206751
ENSE00002366097	52203863	52204012
ENSE00002368554	52205839	52206023
ENSE00002410614	52211283	52211551
ENSE00002421161	52208083	52208247

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.6191 / max 3098.8472, expressed in 1824 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36813	50.3838	1809
36812	22.8933	1813
36811	1.3470	824
36815	0.3384	139
36824	0.2477	98
36816	0.1575	50
36817	0.1357	33
36818	0.0585	14
36814	0.0571	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.58	gold quality
right adrenal gland	UBERON:0001233	99.57	gold quality
left adrenal gland	UBERON:0001234	99.53	gold quality
left adrenal gland cortex	UBERON:0035825	99.53	gold quality
adrenal cortex	UBERON:0001235	99.52	gold quality
adrenal gland	UBERON:0002369	99.24	gold quality
oocyte	CL:0000023	98.98	gold quality
adrenal tissue	UBERON:0018303	98.78	gold quality
secondary oocyte	CL:0000655	97.85	gold quality
right lobe of liver	UBERON:0001114	97.78	gold quality
heart right ventricle	UBERON:0002080	97.57	gold quality
left ventricle myocardium	UBERON:0006566	97.49	gold quality
mucosa of transverse colon	UBERON:0004991	97.15	gold quality
apex of heart	UBERON:0002098	97.02	gold quality
liver	UBERON:0002107	96.98	gold quality
heart left ventricle	UBERON:0002084	96.63	gold quality
cardiac ventricle	UBERON:0002082	96.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.23	gold quality
right atrium auricular region	UBERON:0006631	95.07	gold quality
parotid gland	UBERON:0001831	95.02	gold quality
heart	UBERON:0000948	94.98	gold quality
gastrocnemius	UBERON:0001388	94.86	gold quality
cardiac atrium	UBERON:0002081	94.73	gold quality
vastus lateralis	UBERON:0001379	94.67	gold quality
muscle of leg	UBERON:0001383	94.56	gold quality
biceps brachii	UBERON:0001507	94.53	gold quality
muscle organ	UBERON:0001630	94.42	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.41	gold quality
jejunal mucosa	UBERON:0000399	94.29	gold quality
cerebellar cortex	UBERON:0002129	94.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-84	yes	422.23
E-MTAB-9801	yes	4.26
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, NFIC, NR1H4, NR5A1, NR5A2, PPARA

miRNA regulators (miRDB)

31 targeting ALAS1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-193B-5P	97.91	65.88	837
HSA-MIR-6502-3P	97.86	65.43	569
HSA-MIR-10397-3P	97.78	65.70	601
HSA-MIR-6855-5P	97.51	66.03	830
HSA-MIR-625-3P	97.32	66.55	554
HSA-MIR-3201	97.16	65.42	1044
HSA-MIR-6839-5P	96.74	68.29	1088
HSA-MIR-4791	96.51	67.76	659
HSA-MIR-378J	96.44	66.20	1020

Literature-anchored findings (GeneRIF, showing 20)

• REVIEW:active site and mechanistic analysis, protein folding, structure and function. (PMID:11929042)
• REVIEW: mechanisms involving ALAS deficiency, point mutations, post translational processing, and complex formation with succinyl CoA synthetase subunit B in the pathogenesis of hereditary sideroblastic anemia. (PMID:11929048)
• ALAS expression is regulated by AP-1 complex through sequestration of cAMP-response element protein (CRE)-binding protein (CBP) coactivator in human cells (PMID:12433930)
• ALAS gene expression is regulated by Hepatic nuclear factor 3 and nuclear factor 1 (PMID:15123725)
• First described frameshift ALAS2 mutation, CD506-507 (-C). (PMID:15477213)
• in the liver of Acute liver failure patients, there may be an increase in free heme concentration which down-regulating ALAS1 gene expression (PMID:15547665)
• Alternative splicing of human ALAS1 generates two mRNAs with different 5’-UTRs: a major one, where exon 1B is omitted, and a minor form containing exon 1B. (PMID:15710391)
• 5-aminolevulinate synthase gene repression by the potent tumor promoter, TPA, involves multiple signal transduction pathways (PMID:15797241)
• Expression of candidate genes HPRT1 and ALAS1 in malignant and non-malignant prostate tissue samples after microdissection. (PMID:17628775)
• Differential regulation of human ALAS1 mRNA and protein levels by heme and cobalt protoporphyrin. (PMID:18719978)
• In this study, we show significant reductions of the rate-limiting enzymes involved in heme biosynthesis, ALAS1 in the postmortem cortex of Alzheimer’s disease subjects, providing additional evidence of abnormal heme homeostasis in Alzheimer’s disease. (PMID:19477221)
• The -853T variant functions as an enhancer in the presence of estrogen and speculates that the -1253A variant reduces transcription activity. (PMID:19656447)
• Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. (PMID:21659532)
• These results indicate that ALAS1 is a novel NR5A-target gene and participates in steroid hormone production. (PMID:23024262)
• ALAS1 mRNA and activity were elevated approximately ~3- and 5-fold, and HMB synthase activity was approximately half-normal (~42%) (PMID:26062020)
• the heme-binding site in the N-terminal region of the mature ALAS1 protein is also necessary for the heme-dependent oxidation of ALAS1. (PMID:27496948)
• The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. (PMID:28874591)
• Inhibition of ALAS1 activity exerts anti-tumour effects on colorectal cancer in vitro. (PMID:32270771)
• 5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin. (PMID:33199206)
• Heme-dependent recognition of 5-aminolevulinate synthase by the human mitochondrial molecular chaperone ClpX. (PMID:34704252)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	alas1	ENSDARG00000021059
mus_musculus	Alas1	ENSMUSG00000032786
rattus_norvegicus	Alas1	ENSRNOG00000056596

Paralogs (5): SPTLC1 (ENSG00000090054), GCAT (ENSG00000100116), SPTLC2 (ENSG00000100596), ALAS2 (ENSG00000158578), SPTLC3 (ENSG00000172296)

Protein

Protein identifiers

5-aminolevulinate synthase, non-specific, mitochondrial — P13196 (reviewed: P13196)

Alternative names: 5-aminolevulinic acid synthase 1, Delta-ALA synthase 1, Delta-aminolevulinate synthase 1

All UniProt accessions (4): P13196, H7C4H7, H7C5B0, Q5JAM2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the pyridoxal 5’-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products.

Subunit / interactions. Homodimer. Interacts (hydroxylated form) with VHL.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. In normoxia, is hydroxylated at Pro-576, promoting interaction with VHL, initiating ubiquitination and subsequent degradation via the proteasome. Ubiquitinated; in normoxia following hydroxylation and interaction with VHL, leading to its subsequent degradation via the proteasome.

Activity regulation. Activity increases about 2-fold over 72 hours of hypoxia compared with normoxia. Activity increases in the presence of phenobarbital, chenodeoxycholic and NR1H4/FXR-specific agonist GW4064.

Induction. Up-regulated by bile acids; chenodeoxycholic acid, ursodeoxycholic acid and lithocholic acid and by the NR1H4/FXR-specific agonist GW4064.

Pathway. Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; 5-aminolevulinate from glycine: step 1/1.

Similarity. Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P13196-1	1	yes
P13196-2	2

RefSeq proteins (4): NP_000679, NP_001291372, NP_001291373, NP_954635 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001917	Aminotrans_II_pyridoxalP_BS	Binding_site
IPR004839	Aminotransferase_I/II_large	Domain
IPR010961	4pyrrol_synth_NH2levulA_synth	Domain
IPR015118	5aminolev_synth_preseq	Domain
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR050087	AON_synthase_class-II	Family

Pfam: PF00155, PF09029

Enzyme classification (BRENDA):

• EC 2.3.1.37 — 5-aminolevulinate synthase (BRENDA: 31 organisms, 63 substrates, 127 inhibitors, 243 Km, 111 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLYCINE	0.0003–400	125
SUCCINYL-COA	0.0006–52.4	77
BUTYRYL-COA	0.15–1.4	10
2-HYDROXYBUTANOYL-COA	0.0055–0.0742	4
BUTANOYL-COA	0.0005–0.0093	4
OCTANOYL-COA	0.0018–0.0172	4
GLUTARYL-COA	0.0075–0.0301	3
PYRIDOXAL 5’-PHOSPHATE	0.0008–0.015	3

Catalyzed reactions (Rhea), 1 shown:

• succinyl-CoA + glycine + H(+) = 5-aminolevulinate + CO2 + CoA (RHEA:12921)

UniProt features (25 total): binding site 9, sequence conflict 6, modified residue 2, splice variant 2, transit peptide 1, chain 1, mutagenesis site 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13196-F1	79.80	0.63

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 (1): 445

Ligand- & substrate-binding residues (9): 442 (in other chain); 474; 475; 562; 217; 334; 353; 386 (in other chain); 414 (in other chain)

Post-translational modifications (2): 445, 576

Mutagenesis-validated functional residues (1):

Position	Phenotype
576	loss of interaction with vhl.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis
R-HSA-1989781	PPARA activates gene expression
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 316 (showing top): GOBP_HEMOGLOBIN_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, PID_HNF3B_PATHWAY, ENK_UV_RESPONSE_KERATINOCYTE_UP, REACTOME_METABOLISM_OF_PORPHYRINS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MODULE_335, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS

GO Biological Process (21): response to hypoxia (GO:0001666), obsolete protoporphyrinogen IX biosynthetic process (GO:0006782), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), response to xenobiotic stimulus (GO:0009410), response to herbicide (GO:0009635), response to nickel cation (GO:0010045), response to nutrient levels (GO:0031667), response to cobalt ion (GO:0032025), cellular response to insulin stimulus (GO:0032869), response to gonadotropin (GO:0034698), hemoglobin biosynthetic process (GO:0042541), response to ethanol (GO:0045471), erythrocyte development (GO:0048821), response to cAMP (GO:0051591), response to platinum ion (GO:0070541), response to bile acid (GO:1903412), porphyrin-containing compound metabolic process (GO:0006778), biosynthetic process (GO:0009058), tetrapyrrole biosynthetic process (GO:0033014)

GO Molecular Function (6): 5-aminolevulinate synthase activity (GO:0003870), pyridoxal phosphate binding (GO:0030170), identical protein binding (GO:0042802), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (6): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism of porphyrins	1
Regulation of lipid metabolism by PPARalpha	1
Mitochondrial biogenesis	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to metal ion	3
cellular anatomical structure	3
response to stress	2
heme biosynthetic process	2
response to oxygen-containing compound	2
cytoplasm	2
response to decreased oxygen levels	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
response to chemical	1
response to toxic substance	1
response to stimulus	1
response to insulin	1
cellular response to peptide hormone stimulus	1
response to hormone	1
macromolecule biosynthetic process	1
hemoglobin metabolic process	1
response to alcohol	1
erythrocyte differentiation	1
myeloid cell development	1
response to purine-containing compound	1
response to organophosphorus	1
response to lipid	1
tetrapyrrole metabolic process	1
metabolic process	1
N-succinyltransferase activity	1
anion binding	1
vitamin B6 binding	1
protein binding	1
binding	1
catalytic activity	1
transferase activity	1
nuclear lumen	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2154 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALAS1	HMBS	P08396	917
ALAS1	FECH	P22830	902
ALAS1	ALAD	P13716	864
ALAS1	PPOX	P50336	857
ALAS1	UROD	P06132	839
ALAS1	CPOX	P36551	794
ALAS1	UROS	P10746	771
ALAS1	NPAS2	Q99743	728
ALAS1	NR1D1	P20393	703
ALAS1	BMAL1	O00327	692
ALAS1	GUSB	P08236	671
ALAS1	PER2	O15055	644
ALAS1	OAZ1	P54368	628
ALAS1	CLOCK	O15516	603
ALAS1	FLVCR1	Q9Y5Y0	600

IntAct

257 interactions, top by confidence:

A	B	Type	Score
ALAS1	DUSP19	psi-mi:“MI:0915”(physical association)	0.870
DUSP19	ALAS1	psi-mi:“MI:0915”(physical association)	0.870
CDC73	ALAS1	psi-mi:“MI:0915”(physical association)	0.780
ALAS1	CDC73	psi-mi:“MI:0915”(physical association)	0.780
PPL	ALAS1	psi-mi:“MI:0915”(physical association)	0.720
TMSB10	ALAS1	psi-mi:“MI:0915”(physical association)	0.720
ALAS1	RTL8B	psi-mi:“MI:0915”(physical association)	0.720
LONRF1	ALAS1	psi-mi:“MI:0915”(physical association)	0.720
ZNF564	ALAS1	psi-mi:“MI:0915”(physical association)	0.720
TEKT4	ALAS1	psi-mi:“MI:0915”(physical association)	0.720
ALAS1	ZNF175	psi-mi:“MI:0915”(physical association)	0.720
RTL8B	ALAS1	psi-mi:“MI:0915”(physical association)	0.720
ALAS1	LONRF1	psi-mi:“MI:0915”(physical association)	0.720
ALAS1	ZNF564	psi-mi:“MI:0915”(physical association)	0.720
ALAS1	TEKT4	psi-mi:“MI:0915”(physical association)	0.720
ZNF175	ALAS1	psi-mi:“MI:0915”(physical association)	0.720
ALAS1	TMSB10	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (184): ALAS1 (Two-hybrid), BCL7A (Two-hybrid), PPL (Two-hybrid), TCEA2 (Two-hybrid), TMSB4X (Two-hybrid), TMSB4XP1 (Two-hybrid), TMSB4XP2 (Two-hybrid), TMSB4XP6 (Two-hybrid), WIPF1 (Two-hybrid), ZNF175 (Two-hybrid), TMSB10 (Two-hybrid), USP20 (Two-hybrid), ZFYVE26 (Two-hybrid), POLDIP2 (Two-hybrid), CCHCR1 (Two-hybrid)

ESM2 similar proteins: A0A0U2WCB2, A6NK44, A6QLI6, A8XX92, A9NNH7, B9FK36, O42764, P05165, P07997, P08680, P0DTA4, P13196, P13446, P14882, P16635, P22557, P43090, P54889, Q19842, Q28CR0, Q2KIZ3, Q2QMG2, Q42523, Q42777, Q4KLB0, Q4WHU1, Q502D1, Q553V2, Q5I0C3, Q5R557, Q5R7K1, Q5R9R9, Q612F5, Q63147, Q6CDR5, Q6JQN1, Q759G5, Q872T7, Q8K370, Q91ZA3

Diamond homologs: A0RIB9, A1AQT1, A1WVM6, A3DBD5, A5G6I9, A6LMP4, A6QLI6, A6TU88, A7GSE1, A7HMM1, A7LXM2, A7Z4X1, A7Z5B4, A8MEX7, A9BGL0, A9VG56, B0K590, B0KC20, B1I4F9, B1YMC6, B3EAE0, B3PI88, B4UCB1, B5EEV8, B5Y9Z4, B7HAZ0, B7HNN4, B7ID58, B7IWN1, B7JLX2, B8J637, B9IWY0, B9M8U3, O14092, O31777, O66875, O75600, O88986, O94069, P07997

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	72
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
57771	GRCh38/hg38 3p21.31-14.3(chr3:49461000-55314500)x1	Pathogenic
687764	GRCh37/hg19 3p21.2-21.1(chr3:52195134-52869037)x1	Pathogenic

SpliceAI

1435 predictions. Top by Δscore:

Variant	Effect	Δscore
3:52199439:GA:G	donor_gain	1.0000
3:52199441:G:GG	donor_gain	1.0000
3:52202503:TCA:T	acceptor_loss	1.0000
3:52202505:A:AG	acceptor_gain	1.0000
3:52202506:G:GT	acceptor_gain	1.0000
3:52202506:GA:G	acceptor_gain	1.0000
3:52202506:GAA:G	acceptor_gain	1.0000
3:52202730:GAAAG:G	donor_gain	1.0000
3:52202733:AGGT:A	donor_loss	1.0000
3:52202735:G:GA	donor_loss	1.0000
3:52202735:G:GG	donor_gain	1.0000
3:52202736:T:A	donor_loss	1.0000
3:52203851:C:G	acceptor_gain	1.0000
3:52203855:T:TA	acceptor_gain	1.0000
3:52203858:TCCA:T	acceptor_loss	1.0000
3:52203860:CA:C	acceptor_loss	1.0000
3:52203861:A:AG	acceptor_gain	1.0000
3:52203861:A:T	acceptor_loss	1.0000
3:52203861:AGAG:A	acceptor_gain	1.0000
3:52203862:G:GG	acceptor_gain	1.0000
3:52203862:GA:G	acceptor_gain	1.0000
3:52203862:GAGG:G	acceptor_gain	1.0000
3:52203862:GAGGT:G	acceptor_gain	1.0000
3:52204008:AAAAT:A	donor_gain	1.0000
3:52204009:AAAT:A	donor_gain	1.0000
3:52204009:AAATG:A	donor_loss	1.0000
3:52204010:AAT:A	donor_gain	1.0000
3:52204010:AATG:A	donor_loss	1.0000
3:52204011:AT:A	donor_gain	1.0000
3:52204012:TGTA:T	donor_loss	1.0000

AlphaMissense

4214 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:52204770:T:C	F219L	1.000
3:52204772:T:A	F219L	1.000
3:52204772:T:G	F219L	1.000
3:52204857:T:A	W248R	1.000
3:52204857:T:C	W248R	1.000
3:52204868:T:A	N251K	1.000
3:52204868:T:G	N251K	1.000
3:52204870:A:T	D252V	1.000
3:52205884:T:A	N282K	1.000
3:52205884:T:G	N282K	1.000
3:52211369:T:C	F473L	1.000
3:52211371:C:A	F473L	1.000
3:52211371:C:G	F473L	1.000
3:52204764:C:G	R217G	0.999
3:52204765:G:C	R217P	0.999
3:52204771:T:C	F219S	0.999
3:52204771:T:G	F219C	0.999
3:52204859:G:C	W248C	0.999
3:52204859:G:T	W248C	0.999
3:52204860:T:C	C249R	0.999
3:52204861:G:A	C249Y	0.999
3:52204862:C:G	C249W	0.999
3:52204863:A:C	S250R	0.999
3:52204865:T:A	S250R	0.999
3:52204865:T:G	S250R	0.999
3:52204869:G:C	D252H	0.999
3:52204870:A:C	D252A	0.999
3:52204884:A:C	S257R	0.999
3:52204886:T:A	S257R	0.999
3:52204886:T:G	S257R	0.999

dbSNP variants (sampled 300 via entrez): RS1000023450 (3:52209986 G>A), RS1000263455 (3:52196627 T>C), RS1000338998 (3:52196844 G>C), RS1000521004 (3:52212416 C>G,T), RS1000544499 (3:52203478 T>TTGCAATGAGTC), RS1000580405 (3:52202954 A>G), RS1000975604 (3:52208617 T>C), RS1001063318 (3:52206673 C>A,T), RS1001271227 (3:52214653 C>G), RS1001284314 (3:52199588 A>G), RS1001407665 (3:52206361 A>G), RS1001533603 (3:52200967 C>A,G), RS1001696694 (3:52211608 C>T), RS1001850185 (3:52204765 G>A), RS1001918660 (3:52207140 A>T)

Disease associations

OMIM: gene MIM:125290 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001241_15	Bipolar disorder	2.000000e-06
GCST002149_14	Schizophrenia	1.000000e-08
GCST004521_201	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004902_20	Parkinson’s disease	3.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, increases stability	6
Tretinoin	affects cotreatment, increases expression	5
Benzo(a)pyrene	decreases expression, increases expression	4
perfluorooctane sulfonic acid	increases expression	3
Arsenic Trioxide	increases expression, affects cotreatment	3
Tetrachlorodibenzodioxin	increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
bisphenol A	affects cotreatment, decreases expression, affects expression	2
3,4,5,3’,4’-pentachlorobiphenyl	affects expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Phenobarbital	affects expression, increases expression	2
Rifampin	increases expression	2
Valproic Acid	increases expression, increases methylation, decreases expression, decreases methylation	2
Cyclosporine	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	increases expression	1
hyperforin	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
lead acetate	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	affects expression	1
succinylacetone	decreases reaction, decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
hydrazine	increases expression	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2RF	Abcam HEK293T ALAS1 KO	Transformed cell line	Female
CVCL_SC19	HAP1 ALAS1 (-) 1	Cancer cell line	Male
CVCL_SC20	HAP1 ALAS1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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