ALAD

Summary

ALAD (aminolevulinate dehydratase, HGNC:395) is a protein-coding gene on chromosome 9q32, encoding Delta-aminolevulinic acid dehydratase (P13716). Catalyzes an early step in the biosynthesis of tetrapyrroles.

The ALAD enzyme is composed of 8 identical subunits and catalyzes the condensation of 2 molecules of delta-aminolevulinate to form porphobilinogen (a precursor of heme, cytochromes and other hemoproteins). ALAD catalyzes the second step in the porphyrin and heme biosynthetic pathway; zinc is essential for enzymatic activity. ALAD enzymatic activity is inhibited by lead and a defect in the ALAD structural gene can cause increased sensitivity to lead poisoning and acute hepatic porphyria. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 210 — RefSeq curated summary.

At a glance

• Gene–disease (curated): porphyria due to ALA dehydratase deficiency (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 218 total — 3 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 54
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000031

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:395
Approved symbol	ALAD
Name	aminolevulinate dehydratase
Location	9q32
Locus type	gene with protein product
Status	Approved
Aliases	ALADH, PBGS
Ensembl gene	ENSG00000148218
Ensembl biotype	protein_coding
OMIM	125270
Entrez	210

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 48 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000409155, ENST00000445750, ENST00000448137, ENST00000452726, ENST00000464749, ENST00000468504, ENST00000482001, ENST00000482847, ENST00000494848, ENST00000907358, ENST00000907359, ENST00000907360, ENST00000907361, ENST00000907362, ENST00000907363, ENST00000907364, ENST00000907365, ENST00000907366, ENST00000907367, ENST00000907368, ENST00000907369, ENST00000907370, ENST00000907371, ENST00000907372, ENST00000907373, ENST00000907374, ENST00000907375, ENST00000907376, ENST00000907377, ENST00000907378, ENST00000907379, ENST00000907380, ENST00000907381, ENST00000907382, ENST00000907383, ENST00000907384, ENST00000907385, ENST00000907386, ENST00000907387, ENST00000907388, ENST00000907389, ENST00000907390, ENST00000907391, ENST00000907392, ENST00000907393, ENST00000907394, ENST00000954349, ENST00000954350, ENST00000954351, ENST00000954352, ENST00000954353, ENST00000954354, ENST00000954355

RefSeq mRNA: 3 — MANE Select: NM_000031 NM_000031, NM_001003945, NM_001317745

CCDS: CCDS6794

Canonical transcript exons

ENST00000409155 — 12 exons

Exon	Start	End
ENSE00001878459	113386312	113388361
ENSE00001887546	113401212	113401284
ENSE00003458775	113388977	113389106
ENSE00003486374	113389599	113389686
ENSE00003508566	113390593	113390676
ENSE00003526852	113390405	113390493
ENSE00003539748	113390798	113390933
ENSE00003542680	113389438	113389524
ENSE00003550617	113391527	113391623
ENSE00003563403	113393447	113393634
ENSE00003601973	113389773	113389828
ENSE00003630318	113392119	113392169

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.9831 / max 478.4037, expressed in 1797 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102103	20.8287	1797
102101	0.0922	13
102100	0.0408	6
102102	0.0215	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	98.87	gold quality
right adrenal gland cortex	UBERON:0035827	98.82	gold quality
left adrenal gland	UBERON:0001234	98.53	gold quality
left adrenal gland cortex	UBERON:0035825	98.44	gold quality
adrenal cortex	UBERON:0001235	98.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.14	gold quality
inferior olivary complex	UBERON:0002127	97.54	gold quality
adrenal gland	UBERON:0002369	97.48	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.37	gold quality
spinal cord	UBERON:0002240	97.34	gold quality
parotid gland	UBERON:0001831	97.22	gold quality
trabecular bone tissue	UBERON:0002483	96.32	gold quality
right lobe of liver	UBERON:0001114	96.27	gold quality
substantia nigra	UBERON:0002038	96.11	gold quality
liver	UBERON:0002107	96.04	gold quality
midbrain	UBERON:0001891	95.65	gold quality
medial globus pallidus	UBERON:0002477	95.60	gold quality
amygdala	UBERON:0001876	95.47	gold quality
hypothalamus	UBERON:0001898	95.45	gold quality
body of pancreas	UBERON:0001150	95.43	gold quality
putamen	UBERON:0001874	95.41	gold quality
caudate nucleus	UBERON:0001873	95.28	gold quality
nucleus accumbens	UBERON:0001882	95.19	gold quality
body of stomach	UBERON:0001161	95.16	gold quality
globus pallidus	UBERON:0001875	95.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.76	gold quality
cerebellar hemisphere	UBERON:0002245	94.57	gold quality
apex of heart	UBERON:0002098	94.51	gold quality
heart left ventricle	UBERON:0002084	94.47	gold quality
cerebellar cortex	UBERON:0002129	94.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	yes	55.61
E-MTAB-10042	yes	29.62
E-MTAB-9388	yes	9.51
E-ANND-3	yes	8.60
E-HCAD-10	no	2.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA

miRNA regulators (miRDB)

50 targeting ALAD, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-7977	98.65	66.18	2590

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mechanistic based studies of porphobilinogen synthase with a proposed reaction intermediate analogue inhibitor suggest that the enzyme can be used as a drug target for the treatment of human microbial and parasitic infections. (PMID:11444968)
• Species-specific inhibition of porphobilinogen synthase by 4-oxosebacic acid (PMID:11909869)
• CYP2E1 overexpression up-regulates both this enzyme and heme oxygenase-1 in a human hepatoma cell line. (PMID:12469218)
• The genetic susceptibility of ALAD polymorphism to lead toxicity may exhibit in a lead dose-dependent manner. (PMID:14694653)
• A cross-sectional evaluation of differences of hematologic parameters by ALAD genotype in male lead workers from Korea. (PMID:15064157)
• Finds no association of animolevulinic acid dehydratase polymorphisms with patella lead concentrations in lead workers. (PMID:15213514)
• ALAD polymorphisms not found to be associated with levels of blood lead and blood zinc protoporphyrin in lead workers (PMID:15258767)
• The Porphobilinogen synthase (PBGS) catalyzes the first common reaction in the biosynthesis of the tetrapyrroles, the asymmetric condensation of two molecules of delta-aminolevulinic acid to form porphobilinogen (PMID:15381398)
• Octameric and hexameric morpheeins of PBGS are very close in energy. Also, W19A assembles into a mixture of dimers, which appear to be stable. (PMID:16377642)
• significant interethnic differences in the distribution of G177C ALAD variants found in the Brazilian population is consistent with differences previously reported in other countries (PMID:16445899)
• Homozygote Rsa and Rsa39488 ALAD 2-2 seems to offer some protection against the effect of lead on motor dexterity function. (PMID:16730797)
• Results point out that there is a correlation among diabetes, hypothyroidism and delta-ALA-D activity. (PMID:17291479)
• A negative correlation was found between the alteration in delta-ALA-D activity and oxidative stress (PMID:17383846)
• study found that ALAD polymorphism had a small or only modest effect on blood lead levels in Thai workers who were exposed to lead (PMID:17649958)
• ALAD 1-1 carriers exhibit a greater likelihood than ALAD 1-2/2-2 carriers of psychiatric symptoms at a higher lead burden. (PMID:17823382)
• certain ALAD genotypes may affect the susceptibility of humans to lead (PMID:17966070)
• The morpheein equilibria of wild type (WT) human PBGS are found to respond to changes in pH, PBGS concentration, and substrate turnover. (PMID:18271513)
• Pregnancy is associated with increased plasma lead/whole blood lead ratio in ALAD 1-1 genotype. (PMID:18282196)
• A significant difference was seen in the frequency distribution of ALAD genotype between Uygur and Han races. The genetic susceptibility of ALAD polymorphism to lead toxicity may exhibit in a lead dose-dependent manner. (PMID:18795909)
• ALAD G177C polymorphism along with BLL and assessment of hematological parameters may play an important role in evaluation and better understanding of the consequences of lead exposure. (PMID:19028776)
• genotype was significantly associated with the blood lead concentration (PMID:19440429)
• Polymorphisms of ALAD and VDR gene may play an important role in lead nephrotoxicity in high lead-exposed workers. (PMID:19548578)
• The frequencies of ALAD2 in Asian populations were comparable to those in Caucasians, while Africans had no mutation allele (PMID:19766174)
• ALAD has a major and limiting role in regulating protoporphyrin IX synthesis and photodynamic therapy outcome. (PMID:19789817)
• Allosteric inhibition of human porphobilinogen synthase. (PMID:19812033)
• blood lead levels may be an important risk factor for hypertension and increased systolic and diastolic blood pressure. These associations may be modified by ALAD genotype. (PMID:20123609)
• Lead-exposed workers with the ALAD2 allele appear to be more susceptible to the effects of lead on renal injury, whereas neurobehavioral functions in ALAD1 homozygote tend to be more vulnerable. (PMID:20510440)
• Examined whether the ALAD G177C single nucleotide polymorphism (SNP) affects the relationship between lead and mortality; observed no convincing interaction effect between ALAD genotype and blood lead level on mortality risk. (PMID:21293208)
• ALAD2 and hPEPT2*2 polymorphisms may exaggerate Pb blood burden in boys. (PMID:21327641)
• Study suggests that the lead-exposure-induced increases in ALAD methylation may be involved in the mechanism of lead toxicity. (PMID:21396434)
• ALAD genotype modifies the relationship between Pb and its toxic effects on the peripheral nervous system. This must be considered in the assessment of risks at Pb exposure. (PMID:21439310)
• association between oxidative stress, abnormalities on lipid profile, distribution of body fat and delta-ALA-D activity inhibition; the enzyme is more oxidized in the DM2 patient (PMID:21762684)
• A common genetic variation in ALAD may alter the risk of renal cell carcinoma (PMID:21799727)
• This study demonostrated that modification by the genes ALAD lead-induced cognitive effects in children. (PMID:22101007)
• distribution of a single nucleotide polymorphism in two populations from the Iberian Peninsula (PMID:22298357)
• Workers with the ALAD 1-1 genotype were associated with higher blood lead levels than those with the ALAD 1-2 genotype. (PMID:22851944)
• The results lend support to the notion that ALAD polymorphism exerts no marked impact on lead body burden. (PMID:24156693)
• Genetic variation in ALAD may modify associations between Pb and prostate cancer (PMID:24500903)
• Report the effect of ALAD polymorphism on hematopoietic, hepatic and renal toxicity from lead in occupational exposure workers. (PMID:24631795)
• This study investigated the delta-aminolevulinate dehydratase (delta-ALA-D) activity in whole blood as well as the parameters of oxidative stress, in lung cancer. (PMID:24855033)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	alad	ENSDARG00000100372
mus_musculus	Alad	ENSMUSG00000028393
rattus_norvegicus	Alad	ENSRNOG00000015206
drosophila_melanogaster	Pbgs	FBGN0036271

Protein

Protein identifiers

Delta-aminolevulinic acid dehydratase — P13716 (reviewed: P13716)

Alternative names: Porphobilinogen synthase

All UniProt accessions (6): P13716, A0A140VJL9, B7Z3I9, B7ZBK6, B7ZBK7, B7ZBK8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen.

Subunit / interactions. Homooctamer; active form. Homohexamer; low activity form.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. Acute hepatic porphyria (AHEPP) [MIM:612740] A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Can alternate between a fully active homooctamer and a low-activity homohexamer. A bound magnesium ion may promote the assembly of the fully active homooctamer. The magnesium-binding site is absent in the low-activity homohexamer. Inhibited by compounds that favor the hexameric state. Inhibited by divalent lead ions. The lead ions partially displace the zinc cofactor.

Cofactor. Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. Can bind up to 2 zinc ions per subunit.

Pathway. Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4.

Polymorphism. Genetic variation in ALAD influences susceptibility to lead poisoning in individuals exposed to high amount of environmental lead. There are two common alleles: allele ALAD1 and allele ALAD2 resulting in 3 isozymes: ALAD 1-1, ALAD 1-2, and ALAD 2-2. Individuals with ALAD 1-2 or ALAD 2-2 isozymes have levels of blood lead higher than those in individuals with ALAD 1-1 isozyme. The sequence shown corresponds to allele ALAD*1.

Similarity. Belongs to the ALAD family.

Isoforms (2)

UniProt ID	Names	Canonical?
P13716-1	1	yes
P13716-2	2

RefSeq proteins (3): NP_000022, NP_001003945, NP_001304674 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001731	ALAD	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR030656	ALAD_AS	Active_site

Pfam: PF00490

Enzyme classification (BRENDA):

• EC 4.2.1.24 — porphobilinogen synthase (BRENDA: 79 organisms, 25 substrates, 198 inhibitors, 37 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
5-AMINOLEVULINATE	0.043–2	26
5-AMINOLEVULINIC ACID	0.0003–18	10

Catalyzed reactions (Rhea), 1 shown:

• 2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) (RHEA:24064)

UniProt features (68 total): strand 19, helix 17, binding site 9, sequence variant 7, mutagenesis site 5, turn 4, modified residue 3, active site 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1PV8	X-RAY DIFFRACTION	2.2
5HMS	X-RAY DIFFRACTION	2.8
1E51	X-RAY DIFFRACTION	2.83
5HNR	X-RAY DIFFRACTION	2.83

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13716-F1	96.34	0.94

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 (2): 199 (schiff-base intermediate with substrate); 252 (schiff-base intermediate with substrate)

Ligand- & substrate-binding residues (9): 279; 318; 122; 124; 131; 132; 209; 221; 223

Post-translational modifications (3): 199, 215, 252

Mutagenesis-validated functional residues (5):

Position	Phenotype
122	reduces enzyme activity about 1000000-fold; when associated with a-124 and a-132.
124	reduces enzyme activity about 1000000-fold; when associated with a-122 and a-132.
131	no effect on catalytic activity; when associated with a-223.
132	reduces enzyme activity about 1000000-fold; when associated with a-122 and a-124.
223	no effect on catalytic activity; when associated with a-131.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 391 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ZINC_ION, GNF2_PRDX2, YANG_BREAST_CANCER_ESR1_LASER_UP, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_INTERLEUKIN_4, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_CORTICOSTEROID, REACTOME_METABOLISM_OF_PORPHYRINS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN

GO Biological Process (40): 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 oxidative stress (GO:0006979), response to xenobiotic stimulus (GO:0009410), response to herbicide (GO:0009635), response to iron ion (GO:0010039), response to zinc ion (GO:0010043), response to aluminum ion (GO:0010044), response to ionizing radiation (GO:0010212), response to vitamin B1 (GO:0010266), response to selenium ion (GO:0010269), response to activity (GO:0014823), response to cobalt ion (GO:0032025), response to lipopolysaccharide (GO:0032496), response to vitamin E (GO:0033197), response to amino acid (GO:0043200), response to ethanol (GO:0045471), response to arsenic-containing substance (GO:0046685), response to cadmium ion (GO:0046686), response to mercury ion (GO:0046689), protein homooligomerization (GO:0051260), response to glucocorticoid (GO:0051384), response to methylmercury (GO:0051597), response to platinum ion (GO:0070541), response to fatty acid (GO:0070542), cellular response to lead ion (GO:0071284), cellular response to interleukin-4 (GO:0071353), negative regulation of proteasomal protein catabolic process (GO:1901799), porphyrin-containing compound biosynthetic process (GO:0006779), response to nutrient (GO:0007584), response to toxic substance (GO:0009636), response to hormone (GO:0009725), response to metal ion (GO:0010038), response to lead ion (GO:0010288), response to nutrient levels (GO:0031667), tetrapyrrole biosynthetic process (GO:0033014), response to vitamin (GO:0033273)

GO Molecular Function (7): catalytic activity (GO:0003824), porphobilinogen synthase activity (GO:0004655), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), proteasome core complex binding (GO:1904854), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (8): extracellular region (GO:0005576), nucleus (GO:0005634), cytosol (GO:0005829), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of porphyrins	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to metal ion	4
response to stress	3
cellular anatomical structure	3
heme biosynthetic process	2
response to chemical	2
response to vitamin	2
response to alcohol	2
response to oxygen-containing compound	2
response to decreased oxygen levels	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
response to toxic substance	1
response to radiation	1
response to nitrogen compound	1
response to stimulus	1
response to molecule of bacterial origin	1
response to lipid	1
response to acid chemical	1
molecular_function	1
hydro-lyase activity	1
transition metal ion binding	1
protein binding	1
protein-containing complex binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
secretory granule	1
cytoplasmic vesicle lumen	1
extracellular vesicle	1
intracellular organelle lumen	1
ficolin-1-rich granule	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2120 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALAD	UROD	P06132	975
ALAD	CPOX	P36551	971
ALAD	HMBS	P08396	968
ALAD	UROS	P10746	893
ALAD	FECH	P22830	879
ALAD	ALAS1	P13196	864
ALAD	PPOX	P50336	859
ALAD	ALAS2	P22557	770
ALAD	ACO1	P21399	705
ALAD	AK1	P00568	683
ALAD	PGM3	O95394	631
ALAD	HAMP	P81172	599
ALAD	GATA1	P15976	592
ALAD	EARS2	Q5JPH6	579
ALAD	TFRC	P02786	574

IntAct

17 interactions, top by confidence:

A	B	Type	Score
TPM4	TPM3	psi-mi:“MI:0914”(association)	0.670
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
GMFB	GMFG	psi-mi:“MI:0914”(association)	0.530
ARHGEF35	OBSL1	psi-mi:“MI:0914”(association)	0.530
ALAD	Alad	psi-mi:“MI:0915”(physical association)	0.400
RASGRP2	ALAD	psi-mi:“MI:0915”(physical association)	0.400
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
ISOC2	GTPBP1	psi-mi:“MI:0914”(association)	0.350
ATP6AP2	KLK10	psi-mi:“MI:0914”(association)	0.350
IFNA4	CTSV	psi-mi:“MI:0914”(association)	0.350
ARHGEF35	RFPL4A	psi-mi:“MI:0914”(association)	0.350
TCEAL9	TGM5	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
HUNK	ALAD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (53): ALAD (Affinity Capture-MS), STAT5B (Co-fractionation), ALAD (Affinity Capture-MS), ALAD (Affinity Capture-MS), ALAD (Affinity Capture-MS), ALAD (Affinity Capture-MS), ALAD (Affinity Capture-MS), GPI (Negative Genetic), ALAD (Negative Genetic), HMGCR (Negative Genetic), SKP2 (Positive Genetic), PRKAA1 (Positive Genetic), NDUFB1 (Positive Genetic), CARM1 (Positive Genetic), Alad (Affinity Capture-MS)

ESM2 similar proteins: A0NEF7, A1Z8J0, A8WJ41, B0WAN0, B3MA91, B3NCH1, B3RNT0, B4H1X9, B4HL48, B4IXD3, B4KSL6, B4KXI8, B4LFW2, B4N549, B4PEV9, B5DZN7, B7Q5K1, B8ZXI1, M2XHU6, O14096, O74927, P06214, P07752, P10518, P13716, Q00706, Q09454, Q16RF5, Q24314, Q28DX0, Q29EE9, Q29LT4, Q2TXG3, Q5R998, Q5ZM96, Q6DF96, Q75B32, Q7KRR5, Q7Q727, Q7ZVJ6

Diamond homologs: O26839, O28305, O42768, O67876, O84638, P05373, P06214, P0ACB2, P0ACB3, P0C1R9, P10518, P13716, P24493, P30124, P30950, P42504, P43087, P43210, P45622, P45623, P46723, P54919, P56074, P64333, P64334, P64335, P77923, P77969, P78974, P9WMP4, P9WMP5, Q02250, Q2FXR3, Q42682, Q42836, Q43058, Q55E06, Q58DK5, Q59295, Q59334

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	96
Likely benign	61
Benign	30

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
16866	NM_000031.6(ALAD):c.820G>A (p.Ala274Thr)	Pathogenic
16868	NM_000031.6(ALAD):c.165-11C>A	Pathogenic
16869	NM_000031.6(ALAD):c.165-11C>T	Pathogenic
1068016	NM_000031.6(ALAD):c.481+1G>T	Likely pathogenic
16862	NM_000031.6(ALAD):c.397G>A (p.Gly133Arg)	Likely pathogenic
3067962	NM_000031.6(ALAD):c.165-2A>G	Likely pathogenic

SpliceAI

1648 predictions. Top by Δscore:

Variant	Effect	Δscore
9:113388360:ACC:A	acceptor_loss	1.0000
9:113388361:CCTG:C	acceptor_gain	1.0000
9:113388361:CCTGT:C	acceptor_loss	1.0000
9:113388362:C:CC	acceptor_gain	1.0000
9:113388972:CCTA:C	donor_loss	1.0000
9:113388973:CTACC:C	donor_loss	1.0000
9:113388974:TA:T	donor_loss	1.0000
9:113388975:ACC:A	donor_loss	1.0000
9:113388976:C:CA	donor_loss	1.0000
9:113388976:CCTG:C	donor_gain	1.0000
9:113389102:GGGTG:G	acceptor_gain	1.0000
9:113389103:GGTG:G	acceptor_gain	1.0000
9:113389104:GTG:G	acceptor_gain	1.0000
9:113389105:TG:T	acceptor_gain	1.0000
9:113389107:C:CC	acceptor_gain	1.0000
9:113389107:C:CG	acceptor_loss	1.0000
9:113389108:T:A	acceptor_loss	1.0000
9:113389434:TCA:T	donor_loss	1.0000
9:113389435:CACC:C	donor_loss	1.0000
9:113389436:A:AT	donor_loss	1.0000
9:113389437:C:CT	donor_loss	1.0000
9:113389520:CGGTC:C	acceptor_gain	1.0000
9:113389523:TC:T	acceptor_gain	1.0000
9:113389523:TCC:T	acceptor_loss	1.0000
9:113389524:CC:C	acceptor_gain	1.0000
9:113389524:CCT:C	acceptor_loss	1.0000
9:113389525:C:CC	acceptor_gain	1.0000
9:113389592:CACT:C	donor_loss	1.0000
9:113389593:ACTC:A	donor_loss	1.0000
9:113389595:TCA:T	donor_loss	1.0000

AlphaMissense

2131 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:113389803:T:A	K199I	0.997
9:113389814:G:C	S195R	0.997
9:113389814:G:T	S195R	0.997
9:113389816:T:G	S195R	0.997
9:113391551:A:C	F79L	0.997
9:113391551:A:T	F79L	0.997
9:113391553:A:G	F79L	0.997
9:113389775:G:C	F208L	0.996
9:113389775:G:T	F208L	0.996
9:113389777:A:G	F208L	0.996
9:113389808:A:C	S197R	0.996
9:113389808:A:T	S197R	0.996
9:113389810:T:G	S197R	0.996
9:113390489:A:C	C162W	0.996
9:113390836:T:A	D120V	0.996
9:113389062:A:C	F282L	0.995
9:113389062:A:T	F282L	0.995
9:113389064:A:G	F282L	0.995
9:113393450:A:T	V37D	0.995
9:113389072:G:A	S279F	0.994
9:113389799:A:C	F200L	0.994
9:113389799:A:T	F200L	0.994
9:113389801:A:G	F200L	0.994
9:113390829:G:C	C122W	0.994
9:113390831:A:G	C122R	0.994
9:113393452:A:C	F36L	0.994
9:113393452:A:T	F36L	0.994
9:113393454:A:G	F36L	0.994
9:113389773:C:G	R209P	0.993
9:113390478:G:T	A166D	0.993

dbSNP variants (sampled 300 via entrez): RS1000211567 (9:113389743 C>T), RS1000395329 (9:113395520 C>G,T), RS1000522705 (9:113388460 T>C), RS1000831077 (9:113395797 C>A,T), RS1000851862 (9:113399777 C>G,T), RS1000919914 (9:113401003 G>A), RS1000925282 (9:113399475 G>A), RS1001131617 (9:113392865 T>G), RS1001135659 (9:113394066 G>A), RS1001269496 (9:113392622 A>G,T), RS1001519783 (9:113396246 G>A), RS1001573414 (9:113395027 C>A,T), RS1001676946 (9:113401343 C>A), RS1001940001 (9:113393942 CTCT>C), RS1001954480 (9:113388081 A>AG)

Disease associations

OMIM: gene MIM:125270 | disease phenotypes: MIM:612740

GenCC curated gene-disease

Disease	Classification	Inheritance
porphyria due to ALA dehydratase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
porphyria due to ALA dehydratase deficiency	Moderate	AR

Mondo (1): porphyria due to ALA dehydratase deficiency (MONDO:0013000)

Orphanet (2): Porphyria due to ALA dehydratase deficiency (Orphanet:100924), Acute hepatic porphyria (Orphanet:95157)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000707	Abnormality of the nervous system
HP:0000711	Restlessness
HP:0000713	Agitation
HP:0000716	Depression
HP:0000717	Autism
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000763	Sensory neuropathy
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001271	Polyneuropathy
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001878	Hemolytic anemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002086	Abnormality of the respiratory system
HP:0002093	Respiratory insufficiency
HP:0002203	Respiratory paralysis
HP:0002572	Episodic vomiting
HP:0002902	Hyponatremia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002831_1	Lead levels in blood	4.000000e-14
GCST002831_15	Lead levels in blood	2.000000e-06
GCST90002385_393	High light scatter reticulocyte count	4.000000e-14
GCST90002386_436	High light scatter reticulocyte percentage of red cells	1.000000e-14
GCST90002405_469	Reticulocyte count	9.000000e-12
GCST90002406_284	Reticulocyte fraction of red cells	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562618	Porphyria, Acute Hepatic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3126 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lead	affects reaction, decreases reaction, decreases expression, increases methylation, affects abundance (+4 more)	23
Valproic Acid	increases expression, decreases expression	5
Estradiol	affects cotreatment, increases expression, decreases expression	4
trichostatin A	affects cotreatment, decreases expression, affects expression	3
sodium arsenite	affects expression, decreases expression	3
Cyclosporine	decreases expression	3
bisphenol A	decreases expression	2
Aminolevulinic Acid	affects reaction, increases metabolic processing	2
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	2
Cadmium	affects cotreatment, affects reaction, decreases activity, decreases reaction	2
Carmustine	decreases expression, affects cotreatment, decreases activity	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Diethylstilbestrol	decreases expression	2
Dithiothreitol	affects cotreatment, affects reaction, decreases activity, decreases reaction, increases activity (+1 more)	2
Hydrogen Peroxide	affects expression, increases expression	2
Smoke	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
FR900359	increases phosphorylation	1
acephate	decreases activity	1
glycidyl methacrylate	decreases expression	1
methylselenic acid	increases expression	1
methamidophos	decreases activity	1
afimoxifene	decreases expression, decreases reaction	1
zinc chloride	increases activity, increases reaction, decreases reaction	1
lead nitrate	increases reaction, decreases activity, decreases reaction, increases activity	1
zinc protoporphyrin	affects abundance	1
butyraldehyde	decreases expression	1
bromobenzene	decreases activity	1
triethyllead acetate	increases activity, increases reaction, decreases activity, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2410324	Binding	Inhibition of ALAD (unknown origin)	Synthesis and in vitro cellular uptake of 11C-labeled 5-aminolevulinic acid derivative to estimate the induced cellular accumulation of protoporphyrin IX. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2I0	Abcam Raji ALAD KO	Cancer cell line	Male
CVCL_UQ11	Abcam Jurkat ALAD KO	Cancer cell line	Male
CVCL_WQ95	Abcam K-562 ALAD KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03338816	PHASE3	COMPLETED	ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
NCT03505853	PHASE1	COMPLETED	A Study to Investigate the Interaction Between Givosiran and a 5-probe Drug Cocktail in Patients With Acute Intermittent Porphyria (AIP)
NCT02240784	Not specified	COMPLETED	EXPLORE: A Natural History Study of Acute Hepatic Porphyria (AHP)
NCT03547297	Not specified	TERMINATED	INSIGHT-AHP: A Study to Characterize the Prevalence of Acute Hepatic Porphyria (AHP) in Patients With Clinical Presentation and History Consistent With AHP
NCT04056481	Not specified	APPROVED_FOR_MARKETING	Expanded Access Protocol of Givosiran for Patients With Acute Hepatic Porphyria
NCT04883905	Not specified	RECRUITING	ELEVATE, a Registry of Patients With Acute Hepatic Porphyria (AHP)
NCT04923516	Not specified	COMPLETED	Prevalence of Acute Hepatic Porphyria
NCT05344599	Not specified	ACTIVE_NOT_RECRUITING	Evaluating the Prevalence of Acute Hepatic Porphyria in Postural Tachycardia Syndrome