HMBS

Chr 11ARAD

hydroxymethylbilane synthase

Also known as: ENCEP, LENCEP, PBG-D, PBGD, PORC, UPS

NCBI Gene: 3145ENSG00000256269UniProt: P08397OMIM: 609806

This enzyme catalyzes the third step of heme biosynthesis by polymerizing four porphobilinogen molecules to form hydroxymethylbilane. Mutations cause acute intermittent porphyria and related porphyria syndromes including encephalopathy and leukoencephalopathy, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants, reflecting its essential role in heme production.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAR/ADLOEUF 0.344 OMIM phenotypes
Clinical Summary— HMBS
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Gene-Disease Validity (ClinGen)
acute intermittent porphyria · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
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
0.64Z-score
OE missense 0.87 (0.77–0.99)
179 obs / 204.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.13 (0.06–0.34)
0≤0.351.4
Missense OE0.87 (0.77–0.99)
0≤0.61.4
Synonymous OE1.18
0≤1.21.6
LoF obs/exp: 3 / 22.6Missense obs/exp: 179 / 204.9Syn Z: -1.23
DN
0.4884th %ile
GOF
0.3094th %ile
LOF
0.62top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · LOEUF 0.34

Literature Evidence

LOFDiagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX genePMID:19460837

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Severe peripheral neuropathy secondary to acute intermittent porphyria caused by a rare HMBS gene mutation: a case report.
Li Y et al.·BMC Neurol
2026Case report
Liver Transplantation and Other Hepatically Directed Therapies Do Not Change the Biochemical Phenotype nor Halt Progression of Leukodystrophy due to Biallelic HMBS Variants: A Case Report.
Clark J et al.·JIMD Rep
2026Open AccessCase report
A novel HMBS gene mutation in acute intermittent porphyria: a case report of abdominal pain, seizures, and reversible neuroimaging findings.
Dong W et al.·Front Genet
2025Open AccessCase report
Assessing predictions on fitness effects of missense variants in HMBS in CAGI6.
Zhang J et al.·Hum Genet
2025
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
2024
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients