hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Summary

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (MONDO:0014332) is a disease caused by CA5A (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CA5A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 182
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
Mondo ID	MONDO:0014332
OMIM	615751
Orphanet	401948
SNOMED CT	764456001
UMLS	C4706871
MedGen	1644778
GARD	0013201
Is cancer (heuristic)	no

Also known as: CA-VA deficiency · CA5AD · carbonic anhydrase VA deficiency · carbonic anhydrase VA deficiency, hyperammonemia due to · hyperammonemia due to carbonic anhydrase VA deficiency · hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency · mitochondrial carbonic anhydrase va deficiency

Data availability: 182 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glucose metabolism disease › disorder of gluconeogenesis › hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Related subtypes (6): fructose-1,6-bisphosphatase deficiency, pyruvate carboxylase deficiency disease, glycerol kinase deficiency, infantile form, glycerol kinase deficiency, juvenile form, glycerol kinase deficiency, adult form, phosphoenolpyruvate carboxykinase deficiency

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

182 retrieved; paginated sample, class counts are floors:

79 likely benign, 63 uncertain significance, 13 pathogenic, 11 conflicting classifications of pathogenicity, 8 benign, 5 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069841	NC_000016.9:g.(?87636753)(88505740_?)del	BANP	Pathogenic	criteria provided, single submitter
1069842	NC_000016.9:g.(?87938372)(87960571_?)del	CA5A	Pathogenic	criteria provided, single submitter
127089	NM_001739.2(CA5A):c.619-3421_774+502del	CA5A	Pathogenic	no assertion criteria provided
1457965	NC_000016.9:g.(?87960334)(87970056_?)del	CA5A	Pathogenic	criteria provided, single submitter
1956686	NM_001739.2(CA5A):c.683G>A (p.Trp228Ter)	CA5A	Pathogenic	criteria provided, single submitter
2631113	NM_001739.2(CA5A):c.475T>C (p.Trp159Arg)	CA5A	Pathogenic	criteria provided, single submitter
3243526	NC_000016.9:g.(?87969895)(87970056_?)del	CA5A	Pathogenic	criteria provided, single submitter
3336515	NC_000016.9:g.(?87921618)(87938511_87960353)del	CA5A	Pathogenic	criteria provided, single submitter
3645507	NM_001739.2(CA5A):c.419dup (p.Ser141fs)	CA5A	Pathogenic	criteria provided, single submitter
388645	NM_001739.2(CA5A):c.721G>A (p.Glu241Lys)	CA5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
570252	NM_001739.2(CA5A):c.94C>T (p.Arg32Ter)	CA5A	Pathogenic	criteria provided, multiple submitters, no conflicts
813300	GRCh37/hg19 16q24.2(chr16:87969915-87970056)	CA5A	Pathogenic	criteria provided, single submitter
832363	NC_000016.10:g.(?87888109)(87891974_?)del	CA5A	Pathogenic	criteria provided, single submitter
832389	NC_000016.10:g.(?87904766)(87904924_?)del	CA5A	Pathogenic	criteria provided, single submitter
1705233	NC_000016.9:g.(87925561_87935517)(87970113?)del	CA5A	Likely pathogenic	criteria provided, single submitter
2424226	NC_000016.9:g.(?87935498)(87938530_?)dup	CA5A	Likely pathogenic	criteria provided, single submitter
2503796	NM_001739.2(CA5A):c.618+1G>T	CA5A	Likely pathogenic	criteria provided, single submitter
3670993	NM_001739.2(CA5A):c.459+1G>C	CA5A	Likely pathogenic	criteria provided, single submitter
973554	NM_001739.2(CA5A):c.580C>T (p.Gln194Ter)	CA5A	Likely pathogenic	criteria provided, single submitter
127087	NM_001739.2(CA5A):c.697T>C (p.Ser233Pro)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127088	NM_001739.2(CA5A):c.555G>A (p.Lys185=)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1414664	NM_001739.2(CA5A):c.446C>T (p.Ala149Val)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1495000	NM_001739.2(CA5A):c.514G>T (p.Val172Leu)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1652614	NM_001739.2(CA5A):c.788G>A (p.Arg263His)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2053778	NM_001739.2(CA5A):c.497A>G (p.Asn166Ser)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2201239	NM_001739.2(CA5A):c.283A>G (p.Ile95Val)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
579278	NM_001739.2(CA5A):c.556C>T (p.Leu186Phe)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
793186	NM_001739.2(CA5A):c.543C>T (p.Gly181=)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
798226	NM_001739.2(CA5A):c.172G>A (p.Val58Met)	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
962096	NM_001739.2(CA5A):c.767_774+13del	CA5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
CA5A	Definitive	Autosomal recessive	hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CA5A	Orphanet:401948	Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CA5A	HGNC:1377	ENSG00000174990	P35218	Carbonic anhydrase 5A, mitochondrial	gencc,clinvar
BANP	HGNC:13450	ENSG00000172530	Q8N9N5	Protein BANP	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CA5A	Carbonic anhydrase 5A, mitochondrial	Mitochondrial carbonic anhydrase that catalyzes the reversible conversion of carbon dioxide to bicarbonate/HCO3.
BANP	Protein BANP	Controls V(D)J recombination during T-cell development by repressing T-cell receptor (TCR) beta enhancer function.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CA5A	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
BANP	Other/Unknown	no		BEN_domain, BANP

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1
blood	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CA5A	87		marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
BANP	277	ubiquitous	marker	oocyte, secondary oocyte, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BANP	1,562
CA5A	1,165

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BANP	Q8N9N5	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CA5A	P35218	84.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Reversible hydration of carbon dioxide	1	475.8×	0.011	CA5A
Regulation of TP53 Activity through Association with Co-factors	1	407.9×	0.011	BANP
Degradation of CDH1	1	98.5×	0.030	BANP
Regulation of TP53 Activity	1	66.4×	0.034	BANP
Transcriptional Regulation by TP53	1	31.0×	0.058	BANP
RNA Polymerase II Transcription	1	11.3×	0.130	BANP
Gene expression (Transcription)	1	8.9×	0.140	BANP
Generic Transcription Pathway	1	7.5×	0.144	BANP
Metabolism	1	5.8×	0.165	CA5A

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
chromatin organization	1	99.1×	0.010	BANP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CA5A	METHAZOLAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CA5A	51	4
BANP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
METHAZOLAMIDE	4	CA5A
ACETAZOLAMIDE	4	CA5A
ZONISAMIDE	4	CA5A
ETHOXZOLAMIDE	4	CA5A
TOPIRAMATE	4	CA5A
TRICHLORMETHIAZIDE	4	CA5A
CHLORTHALIDONE	4	CA5A
FLUDARABINE PHOSPHATE	4	CA5A
CELECOXIB	4	CA5A
PYRITHIONE ZINC	4	CA5A
RUFINAMIDE	4	CA5A
LEVETIRACETAM	4	CA5A
LENVATINIB	4	CA5A
DICHLORPHENAMIDE	4	CA5A
SULFANILAMIDE	4	CA5A
VERALIPRIDE	4	CA5A
DORZOLAMIDE	4	CA5A
BRINZOLAMIDE	4	CA5A
NILOTINIB	4	CA5A
SULPIRIDE	4	CA5A
BORTEZOMIB	4	CA5A
FUROSEMIDE	4	CA5A
INDAPAMIDE	4	CA5A
MAFENIDE	4	CA5A
HYDROXYUREA	4	CA5A
HYDROQUINONE	4	CA5A
LACOSAMIDE	4	CA5A
TRIENTINE	4	CA5A
COUMARIN	4	CA5A
VALDECOXIB	4	CA5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CA5A	144	Binding:143, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CA5A	4.2.1.1	carbonic anhydrase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CA5A	144

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
METHAZOLAMIDE	4	CA5A
ACETAZOLAMIDE	4	CA5A
ZONISAMIDE	4	CA5A
ETHOXZOLAMIDE	4	CA5A
TOPIRAMATE	4	CA5A
TRICHLORMETHIAZIDE	4	CA5A
CHLORTHALIDONE	4	CA5A
FLUDARABINE PHOSPHATE	4	CA5A
CELECOXIB	4	CA5A
PYRITHIONE ZINC	4	CA5A
RUFINAMIDE	4	CA5A
LEVETIRACETAM	4	CA5A
LENVATINIB	4	CA5A
DICHLORPHENAMIDE	4	CA5A
SULFANILAMIDE	4	CA5A
VERALIPRIDE	4	CA5A
DORZOLAMIDE	4	CA5A
BRINZOLAMIDE	4	CA5A
NILOTINIB	4	CA5A
SULPIRIDE	4	CA5A
BORTEZOMIB	4	CA5A
FUROSEMIDE	4	CA5A
INDAPAMIDE	4	CA5A
MAFENIDE	4	CA5A
HYDROXYUREA	4	CA5A
HYDROQUINONE	4	CA5A
LACOSAMIDE	4	CA5A
TRIENTINE	4	CA5A
COUMARIN	4	CA5A
VALDECOXIB	4	CA5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CA5A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BANP

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)
BANP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns