ALAD

aminolevulinate dehydratase

Basic information

Region (hg38): 9:113386312-113401290

Links

ENSG00000148218 ∙ NCBI:210 ∙ OMIM:125270 ∙ HGNC:395 ∙ Uniprot:P13716 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• porphyria due to ALA dehydratase deficiency (Strong), mode of inheritance: AR
• porphyria due to ALA dehydratase deficiency (Moderate), mode of inheritance: AR
• porphyria due to ALA dehydratase deficiency (Strong), mode of inheritance: AR
• porphyria due to ALA dehydratase deficiency (Supportive), mode of inheritance: AR
• porphyria due to ALA dehydratase deficiency (Limited), mode of inheritance: AR
• porphyria due to ALA dehydratase deficiency (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Porphyria, acute hepatic	AR	Biochemical; Pharmacogenomic	Medical treatment (eg, with agents such as infusion of heme arginate) can be effective; Affected individuals are endangered by certain agents, including alcohol ingestion or lead exposure	Biochemical; Gastrointestinal; Neurologic	513604; 3559484; 2600550; 2063868; 7490911; 9732973; 1905639; 1716854; 1569184; 9516683; 11071662; 10706561; 11342419; 15303011; 16343966; 16398658; 17236137; 17366816
Digenic inheritance (with CPOX) has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALAD gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALAD gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	28	6	37
missense		1	42	3		46
nonsense						0
start loss			1			1
frameshift						0
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2				2
splice region				1	1	2
non coding			33	21	23	77
Total	0	3	80	52	29

Variants in ALAD

This is a list of pathogenic ClinVar variants found in the ALAD region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-113386350-C-T		Porphobilinogen synthase deficiency	Benign (Jan 13, 2018)
9-113386384-GT-G		Porphobilinogen synthase deficiency	Uncertain significance (Jun 14, 2016)
9-113386436-T-G		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386468-A-G		Porphobilinogen synthase deficiency	Uncertain significance (Jan 12, 2018)
9-113386487-CTT-C		Porphobilinogen synthase deficiency	Likely benign (Jun 14, 2016)
9-113386496-A-G		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386497-T-C		Porphobilinogen synthase deficiency	Likely benign (Jan 12, 2018)
9-113386513-T-G		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386559-C-T		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386563-A-G		Porphobilinogen synthase deficiency	Benign (Jan 12, 2018)
9-113386625-G-A		Porphobilinogen synthase deficiency	Uncertain significance (Jan 12, 2018)
9-113386629-T-A		Porphobilinogen synthase deficiency	Uncertain significance (Jan 12, 2018)
9-113386669-C-T		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386789-A-G		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386827-C-T		Porphobilinogen synthase deficiency	Likely benign (Jan 13, 2018)
9-113386830-C-T		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386836-T-C		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113386919-C-T		Porphobilinogen synthase deficiency	Likely benign (Jan 13, 2018)
9-113386978-C-T		Porphobilinogen synthase deficiency	Conflicting classifications of pathogenicity (Jan 01, 2023)
9-113387020-C-G		Porphobilinogen synthase deficiency	Uncertain significance (Jan 12, 2018)
9-113387020-C-T		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113387293-C-T		Porphobilinogen synthase deficiency	Uncertain significance (Jan 13, 2018)
9-113387380-G-A		Porphobilinogen synthase deficiency	Uncertain significance (Jan 12, 2018)
9-113387429-G-T		Porphobilinogen synthase deficiency	Benign (Jan 12, 2018)
9-113387487-T-C		Porphobilinogen synthase deficiency	Benign (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALAD	protein_coding	protein_coding	ENST00000409155	11	15017

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000562	0.974	125713	0	21	125734	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.23	157	207	0.759	0.0000141	2124
Missense in Polyphen		64	88.517	0.72302		908
Synonymous	0.143	78	79.6	0.980	0.00000502	675
Loss of Function	2.00	10	19.5	0.512	0.00000114	210

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000207	0.000206
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.0000800	0.0000791
Middle Eastern	0.00	0.00
South Asian	0.000163	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: 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. {ECO:0000269|PubMed:11032836, ECO:0000269|PubMed:19812033}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:10706561, ECO:0000269|PubMed:1309003, ECO:0000269|PubMed:1569184, ECO:0000269|PubMed:17236137, ECO:0000269|PubMed:2063868}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Porphyrin and chlorophyll metabolism - Homo sapiens (human);Hereditary Coproporphyria (HCP);Porphyria Variegata (PV);Congenital Erythropoietic Porphyria (CEP) or Gunther Disease;Acute Intermittent Porphyria;Porphyrin Metabolism;Heme Biosynthesis;Neutrophil degranulation;hemoglobins chaperone;Heme biosynthesis;Metabolism of porphyrins;Innate Immune System;Immune System;Metabolism;Porphyrin metabolism;tetrapyrrole biosynthesis;heme biosynthesis (Consensus)

Recessive Scores

• pRec: 0.559

Intolerance Scores

• loftool: 0.133
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.54

Haploinsufficiency Scores

• pHI: 0.119
• hipred: N
• hipred_score: 0.476
• ghis: 0.529

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.945

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Alad

Gene ontology

• Biological process: response to hypoxia;protoporphyrinogen IX biosynthetic process;heme biosynthetic process;response to oxidative stress;response to herbicide;response to iron ion;response to zinc ion;response to aluminum ion;response to ionizing radiation;response to vitamin B1;response to selenium ion;response to activity;response to cobalt ion;response to lipopolysaccharide;response to vitamin E;response to amino acid;neutrophil degranulation;response to ethanol;response to arsenic-containing substance;response to cadmium ion;response to mercury ion;protein homooligomerization;response to glucocorticoid;response to methylmercury;response to platinum ion;response to fatty acid;cellular response to lead ion;cellular response to interleukin-4;negative regulation of proteasomal protein catabolic process
• Cellular component: extracellular region;nucleus;cytosol;secretory granule lumen;extracellular exosome;ficolin-1-rich granule lumen
• Molecular function: catalytic activity;porphobilinogen synthase activity;zinc ion binding;identical protein binding;proteasome core complex binding