hyperphenylalaninemia due to DNAJC12 deficiency

Summary

hyperphenylalaninemia due to DNAJC12 deficiency (MONDO:0044304) is a disease caused by DNAJC12 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNAJC12 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphenylalaninemia due to DNAJC12 deficiency
Mondo ID	MONDO:0044304
OMIM	617384
Orphanet	508523
UMLS	C4479270
MedGen	1391882
GARD	0017950
Is cancer (heuristic)	no

Also known as: HPANBH4 · hyperphenylalaninemia due to DNAJC12 deficiency

Data availability: 18 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

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 › hyperphenylalaninemia due to DNAJC12 deficiency

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, glycine encephalopathy, aminoacylase 1 deficiency, adenine phosphoribosyltransferase deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

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

18 retrieved; paginated sample, class counts are floors:

13 pathogenic, 3 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1185914	NM_021800.3(DNAJC12):c.410_413del (p.Lys137fs)	DNAJC12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3374776	NM_021800.3(DNAJC12):c.411del (p.Glu138fs)	DNAJC12	Pathogenic	criteria provided, single submitter
3764628	NM_021800.3(DNAJC12):c.157+2T>C	DNAJC12	Pathogenic	criteria provided, single submitter
393301	NM_021800.3(DNAJC12):c.298-968_503-2603del	DNAJC12	Pathogenic	no assertion criteria provided
393302	NM_021800.3(DNAJC12):c.215G>C (p.Arg72Pro)	DNAJC12	Pathogenic	no assertion criteria provided
393303	NM_021800.3(DNAJC12):c.158-2A>T	DNAJC12	Pathogenic	no assertion criteria provided
636261	NM_021800.3(DNAJC12):c.58_59del (p.Gly20fs)	DNAJC12	Pathogenic	no assertion criteria provided
694071	NM_021800.3(DNAJC12):c.85del (p.Gln29fs)	DNAJC12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694072	NM_021800.3(DNAJC12):c.596G>T (p.Ter199Leu)	DNAJC12	Pathogenic	no assertion criteria provided
694073	NM_021800.3(DNAJC12):c.214C>T (p.Arg72Ter)	DNAJC12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694074	NM_021800.3(DNAJC12):c.187A>T (p.Lys63Ter)	DNAJC12	Pathogenic	criteria provided, single submitter
694075	NM_021800.3(DNAJC12):c.79-2A>G	DNAJC12	Pathogenic	no assertion criteria provided
870653	NM_021800.3(DNAJC12):c.298-2A>C	DNAJC12	Pathogenic	no assertion criteria provided
870654	NM_021800.3(DNAJC12):c.502+1G>C	DNAJC12	Pathogenic	criteria provided, single submitter
870655	NM_021800.3(DNAJC12):c.524G>A (p.Trp175Ter)	DNAJC12	Pathogenic	criteria provided, multiple submitters, no conflicts
870656	NM_021800.3(DNAJC12):c.309G>T (p.Trp103Cys)	DNAJC12	Pathogenic	no assertion criteria provided
785319	NM_021800.3(DNAJC12):c.430G>A (p.Ala144Thr)	DNAJC12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802579	NM_021800.3(DNAJC12):c.124C>T (p.His42Tyr)	DNAJC12	Uncertain significance	criteria provided, single submitter

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
DNAJC12	Definitive	Autosomal recessive	hyperphenylalaninemia due to DNAJC12 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJC12	Orphanet:508523	Hyperphenylalaninemia due to DNAJC12 deficiency

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
DNAJC12	HGNC:28908	ENSG00000108176	Q9UKB3	DnaJ homolog subfamily C member 12	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJC12	DnaJ homolog subfamily C member 12	Probable co-chaperone that participates in the proper folding of biopterin-dependent aromatic amino acid hydroxylases, which include phenylalanine-4-hydroxylase (PAH), tyrosine 3-monooxygenase (TH) and peripheral and neuronal tryptophan hy…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAJC12	Other/Unknown	no		DnaJ_domain, JDP1-like, J_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar vermis	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJC12	250	ubiquitous	marker	islet of Langerhans, cerebellar vermis, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJC12	1,059

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNAJC12	Q9UKB3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNAJC12	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	DNAJC12

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)
DNAJC12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.