Histidinemia

Summary

Histidinemia (MONDO:0009345) is a disease with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 107
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Validated
Prevalence at birth	1-9 / 100 000	2.7	Sweden	Validated
Prevalence at birth	1-9 / 100 000	8.3	United States	Validated
Prevalence at birth	1-5 / 10 000	11.9	Japan	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0002927	Histidinuria	Obligate (100%)
HP:0010906	Hyperhistidinemia	Obligate (100%)
HP:0000708	Atypical behavior	Very rare (<1-4%)
HP:0000752	Hyperactivity	Very rare (<1-4%)
HP:0001328	Specific learning disability	Very rare (<1-4%)
HP:0002167	Abnormality of speech or vocalization	Very rare (<1-4%)
HP:0011343	Moderate global developmental delay	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	histidinemia
Mondo ID	MONDO:0009345
MeSH	C538320
OMIM	235800
Orphanet	2157
DOID	DOID:0060168
ICD-10-CM	E70.41
ICD-11	261052955
SNOMED CT	410058007
UMLS	C0220992
MedGen	113135
GARD	0006661
NORD	1245
Is cancer (heuristic)	no

Also known as: Hal deficiency · HIS deficiency · histidase deficiency · histidine ammonia-lyase deficiency · histidinemia · Histidinuria · histidinuria · hyperhistidinemia

Data availability: 107 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of histidine metabolism › histidinemia

Related subtypes (1): urocanic aciduria

Subtypes (1): histidinuria due to a renal tubular defect

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

107 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 11 benign, 9 likely benign, 5 conflicting classifications of pathogenicity, 4 affects, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3775254	NM_002108.4(HAL):c.1520-5_1538del	HAL	Likely pathogenic	criteria provided, single submitter
310711	NM_002108.4(HAL):c.1106G>A (p.Arg369Gln)	HAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310714	NM_002108.4(HAL):c.855+9C>T	HAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310722	NM_002108.4(HAL):c.398G>A (p.Arg133His)	HAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732015	NM_002108.4(HAL):c.1584G>A (p.Thr528=)	HAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
779267	NM_002108.4(HAL):c.715+9A>G	HAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1689	NM_002108.4(HAL):c.617G>C (p.Arg206Thr)	HAL	Affects	no assertion criteria provided
1690	NM_002108.4(HAL):c.623G>T (p.Arg208Leu)	HAL	Affects	no assertion criteria provided
1691	NM_002108.4(HAL):c.776C>T (p.Pro259Leu)	HAL	Affects	no assertion criteria provided
1692	NM_002108.4(HAL):c.965G>C (p.Arg322Pro)	HAL	Affects	no assertion criteria provided
2432363	NM_002108.4(HAL):c.578C>G (p.Ser193Ter)	HAL	Uncertain significance	criteria provided, single submitter
2444415	NM_002108.4(HAL):c.1018G>A (p.Val340Met)	HAL	Uncertain significance	criteria provided, single submitter
310671	NM_002108.4(HAL):c.*1548G>A	HAL	Uncertain significance	criteria provided, single submitter
310672	NM_002108.4(HAL):c.*1518C>T	HAL	Uncertain significance	criteria provided, single submitter
310674	NM_002108.4(HAL):c.*1489A>C	HAL	Uncertain significance	criteria provided, single submitter
310675	NM_002108.4(HAL):c.*1409G>A	HAL	Uncertain significance	criteria provided, single submitter
310676	NM_002108.4(HAL):c.*1359C>A	HAL	Uncertain significance	criteria provided, single submitter
310678	NM_002108.4(HAL):c.*1283T>C	HAL	Uncertain significance	criteria provided, single submitter
310681	NM_002108.4(HAL):c.*1169G>T	HAL	Uncertain significance	criteria provided, single submitter
310682	NM_002108.4(HAL):c.*1161C>T	HAL	Uncertain significance	criteria provided, single submitter
310684	NM_002108.4(HAL):c.*976T>G	HAL	Uncertain significance	criteria provided, single submitter
310686	NM_002108.4(HAL):c.*789G>A	HAL	Uncertain significance	criteria provided, single submitter
310687	NM_002108.4(HAL):c.*756C>T	HAL	Uncertain significance	criteria provided, single submitter
310688	NM_002108.4(HAL):c.*728T>A	HAL	Uncertain significance	criteria provided, single submitter
310690	NM_002108.4(HAL):c.*603A>G	HAL	Uncertain significance	criteria provided, single submitter
310691	NM_002108.4(HAL):c.*555G>A	HAL	Uncertain significance	criteria provided, single submitter
310692	NM_002108.4(HAL):c.*509A>T	HAL	Uncertain significance	criteria provided, single submitter
310693	NM_002108.4(HAL):c.*428C>G	HAL	Uncertain significance	criteria provided, single submitter
310697	NM_002108.4(HAL):c.*392C>T	HAL	Uncertain significance	criteria provided, multiple submitters, no conflicts
310698	NM_002108.4(HAL):c.*227A>C	HAL	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HAL	Moderate	Autosomal dominant	histidinemia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HAL	Orphanet:2157	Histidinemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HAL	HGNC:4806	ENSG00000084110	P42357	Histidine ammonia-lyase	gencc,clinvar

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HAL	Enzyme (other)	yes	4.3.1.3	Aromatic_Lyase, HutH, L-Aspartase-like

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
penis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HAL	181	tissue_specific	yes	right lobe of liver, penis, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HAL	2,254

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HAL	P42357	90.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Histidine catabolism	1	1142.0×	9e-04	HAL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-histidine catabolic process to glutamate and formamide	1	4213.0×	4e-04	HAL
obsolete L-histidine catabolic process to glutamate and formate	1	4213.0×	4e-04	HAL
L-histidine catabolic process	1	2407.4×	4e-04	HAL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HAL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HAL	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HAL	4.3.1.3	histidine ammonia-lyase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	HAL
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HAL	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.