HMBS

Chr 11ARAD

hydroxymethylbilane synthase

NCBI Gene: 3145ENSG00000256269UniProt: P08397

As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen (PubMed:18004775, PubMed:18936296, PubMed:19138865, PubMed:23815679). Catalysis begins with the assembly of the dipyrromethane cofactor by the apoenzyme from two molecules of porphobilinogen or from preuroporphyrinogen. The covalently linked cofactor acts as a primer, around which the tetrapyrrole product is assembled (PubMed:18936296). In the last step of catalysis, the product, preuroporphyrinogen, is released, leaving the cofactor bound to the holodeaminase intact (PubMed:18936296)

Primary Disease Associations & Inheritance

Encephalopathy, porphyria-relatedMIM #620704
AR
Leukoencephalopathy, porphyria-relatedMIM #620711
AR
Porphyria, acute intermittentMIM #176000
AD
Porphyria, acute intermittent, nonerythroid variantMIM #176000
AD
793
ClinVar variants
97
Pathogenic / LP
0.95
pLI score· haploinsufficient
1
Active trials
Clinical Summary— HMBS
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 212 VUS of 793 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.34LOEUF
pLI 0.949
Z-score 3.82
OE 0.13 (0.06–0.34)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.64Z-score
OE missense 0.87 (0.77–0.99)
179 obs / 204.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.06–0.34)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.77–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.18
0≤1.21.6
LoF obs/exp: 3 / 22.6Missense obs/exp: 179 / 204.9Syn Z: -1.23

ClinVar Variant Classifications

793 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic73
Likely Pathogenic24
VUS212
Likely Benign164
Benign12
Conflicting3
73
Pathogenic
24
Likely Pathogenic
212
VUS
164
Likely Benign
12
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
48
6
19
0
73
Likely Pathogenic
12
7
5
0
24
VUS
3
157
47
5
212
Likely Benign
0
2
94
68
164
Benign
0
0
12
0
12
Conflicting
—3
Total6317217773488

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

View in ClinVar →

Protein Context — Lollipop Plot

HMBS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Encephalopathy, porphyria-related

MIM #620704

Molecular basis of disorder known

Autosomal recessive

Leukoencephalopathy, porphyria-related

MIM #620711

Molecular basis of disorder known

Autosomal recessive

Porphyria, acute intermittent

MIM #176000

Molecular basis of disorder known

Autosomal dominant

Porphyria, acute intermittent, nonerythroid variant

MIM #176000

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review.
Wang B et al.·Gastroenterology
2023Review
Identification and validation of extracellular vesicle reference genes for the normalization of RT-qPCR data.
Pinheiro C et al.·J Extracell Vesicles
2024
Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.
van Loggerenberg W et al.·Am J Hum Genet
2023Functional
Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators.
Bustad HJ et al.·Int J Mol Sci
2021Review
Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.
Stutterd CA et al.·Am J Med Genet A
2021
Emerging therapies for acute intermittent porphyria.
Fontanellas A et al.·Expert Rev Mol Med
2016Review
Neurodevelopmental disorder in a patient with HMBS and SCN3A variants-A possibly blended phenotype further delineating autosomal recessive HMBS related disease.
M K et al.·Am J Med Genet A
2024Case report
Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.
Molina L et al.·J Hepatol
2022
Recommendations for the establishment and operation of a donor human milk bank.
Arslanoglu S et al.·Nutr Rev
2023
Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer.
Astiazaran-Symonds E et al.·JCO Precis Oncol
2022Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Acute Intermittent Porphyria (AIP)

Identification of Acute Intermittent Porphyria Modifying Genes

RECRUITING
NCT05502133Icahn School of Medicine at Mount SinaiStarted 2022-09-23

External Resources

Links to major genomics databases and tools