ALAD

Chr 9AR

aminolevulinate dehydratase

Also known as: ALADH, PBGS

NCBI Gene: 210 ENSG00000148218 OMIM: 125270

The ALAD enzyme catalyzes the condensation of two molecules of delta-aminolevulinate to form porphobilinogen in the second step of heme biosynthesis, requiring zinc for activity. Biallelic mutations cause acute hepatic porphyria and increased susceptibility to lead poisoning through autosomal recessive inheritance. The gene is loss-of-function tolerant (pLI near 0), consistent with recessive disease requiring complete loss of enzyme function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.872 OMIM phenotypes

Clinical Summary— ALAD

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Gene-Disease Validity (ClinGen)

porphyria due to ALA dehydratase deficiency · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 92 VUS of 215 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.00

OE 0.51 (0.32–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.23Z-score

OE missense 0.76 (0.67–0.87)

157 obs / 206.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.32–0.87)

0≤0.351.4

Missense OE?0.76 (0.67–0.87)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 10 / 19.5Missense obs/exp: 157 / 206.8Syn Z: 0.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedALAD-related acute hepatic porphyriaOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.76top 25%

GOF

0.4677th %ile

LOF

0.2582th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

215 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic3

VUS92

Likely Benign67

Benign30

Conflicting10

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	2	0	3
Likely Pathogenic	2	1	0	0	3
VUS	0	59	30	3	92
Likely Benign	1	5	23	38	67
Benign	0	0	25	5	30
Conflicting	—				10
Total	3	66	80	46	205

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

29 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap ALAD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →