HMBS

Chr 11ARAD

hydroxymethylbilane synthase

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

NCBI Gene: 3145 ENSG00000256269 UniProt: P08397 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

181 unique Pathogenic / Likely Pathogenic· 270 VUS of 755 total submissions

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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 OE?0.13 (0.06–0.34)

0≤0.351.4

Missense OE?0.87 (0.77–0.99)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 3 / 22.6Missense obs/exp: 179 / 204.9Syn Z: -1.23

This gene — mechanism propensity

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 · 66% of P/LP variants are LoF · LOEUF 0.34 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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 gene1

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

References

1.PMID 19460837 ↗

ClinVar Variant Classifications

755 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic132

Likely Pathogenic49

VUS270

Likely Benign243

Benign26

Conflicting23

132

Pathogenic

Likely Pathogenic

270

VUS

243

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	99	25	8	0	132
Likely Pathogenic	21	23	5	0	49
VUS	5	207	49	9	270
Likely Benign	0	5	136	102	243
Benign	0	0	23	3	26
Conflicting	—				23
Total	125	260	221	114	743

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap HMBS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →