Hyperprolinemia type 2

Summary

Hyperprolinemia type 2 (MONDO:0009401) is a disease caused by ALDH4A1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ALDH4A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 321
• Phenotypes (HPO): 51

Clinical features

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002921	Abnormality of the cerebrospinal fluid	Very frequent (80-99%)
HP:0003080	Hydroxyprolinuria	Very frequent (80-99%)
HP:0003137	Prolinuria	Very frequent (80-99%)
HP:0008358	Hyperprolinemia	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0012402	Increased urine alpha-ketoglutarate concentration	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0002154	Hyperglycinemia	Frequent (30-79%)
HP:0002197	Generalized-onset seizure	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002922	Increased CSF protein concentration	Frequent (30-79%)
HP:0003348	Hyperalaninemia	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0008326	Reduced circulating vitamin B6 level	Frequent (30-79%)
HP:0011199	EEG with generalized sharp slow waves	Frequent (30-79%)
HP:0012432	Chronic fatigue	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000511	Vertical supranuclear gaze palsy	Occasional (5-29%)
HP:0000597	Ophthalmoparesis	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001345	Psychotic mentation	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002133	Status epilepticus	Occasional (5-29%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Occasional (5-29%)
HP:0002490	Increased CSF lactate	Occasional (5-29%)
HP:0002936	Distal sensory impairment	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0009088	Speech articulation difficulties	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0011152	Early onset absence seizures	Occasional (5-29%)
HP:0011342	Mild global developmental delay	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperprolinemia type 2
Mondo ID	MONDO:0009401
MeSH	C538385
OMIM	239510
Orphanet	79101
DOID	DOID:0080543
SNOMED CT	717181004
UMLS	C2931835
MedGen	419175
GARD	0006710
MedDRA	10058512, 10058514
Is cancer (heuristic)	no

Also known as: 1 alpha pyrroline-5-carboxylate dehydrogenase deficiency · 1-pyrroline-5-carboxylate dehydrogenase activity disease · ALDH4A1 hyperprolinemia · delta-1-pyrroline-5-carboxylate dehydrogenase deficiency · delta1-pyrroline-5-carboxylate dehydrogenase deficiency · disorder of 1-pyrroline-5-carboxylate dehydrogenase activity · HPII · hyperprolinemia caused by mutation in ALDH4A1 · hyperprolinemia type 2 · hyperprolinemia, type II · HYRPRO2 · type 2 hyperprolinemia

Data availability: 321 ClinVar variants · 6 GenCC gene-disease records.

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 › inborn disorder of proline metabolism › hyperprolinemia › hyperprolinemia type 2

Related subtypes (1): hyperprolinemia type 1

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

321 retrieved; paginated sample, class counts are floors:

117 uncertain significance, 111 likely benign, 31 benign, 30 conflicting classifications of pathogenicity, 16 likely pathogenic, 8 benign/likely benign, 5 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333353	NM_003748.4(ALDH4A1):c.139C>T (p.Arg47Ter)	ALDH4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526027	NM_003748.4(ALDH4A1):c.72del (p.Arg23_Trp24insTer)	ALDH4A1	Pathogenic	criteria provided, single submitter
2424756	NC_000001.10:g.(?19199339)(19201095_?)del	ALDH4A1	Pathogenic	criteria provided, single submitter
3633307	NM_003748.4(ALDH4A1):c.451C>T (p.Gln151Ter)	ALDH4A1	Pathogenic	criteria provided, single submitter
3705082	NM_003748.4(ALDH4A1):c.960_964del (p.His321fs)	ALDH4A1	Pathogenic	criteria provided, single submitter
4002	NM_003748.4(ALDH4A1):c.1560dup (p.Gly521fs)	ALDH4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438800	NM_003748.4(ALDH4A1):c.866+1G>A	ALDH4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4770797	NM_003748.4(ALDH4A1):c.200del (p.Val67fs)	ALDH4A1	Pathogenic	criteria provided, single submitter
1809608	NM_003748.4(ALDH4A1):c.363_370dup (p.Arg124fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
2627894	NM_003748.4(ALDH4A1):c.240C>G (p.Tyr80Ter)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574718	NM_003748.4(ALDH4A1):c.1580-2A>G	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574732	NM_003748.4(ALDH4A1):c.1333A>T (p.Lys445Ter)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574737	NM_003748.4(ALDH4A1):c.1152dup (p.Gly385fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574741	NM_003748.4(ALDH4A1):c.1137delC (p.Pro380fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574746	NM_003748.4(ALDH4A1):c.1057dup (p.Arg353fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574753	NM_003748.4(ALDH4A1):c.689_696dup (p.Lys233fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574758	NM_003748.4(ALDH4A1):c.551dup (p.Pro185fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574763	NM_003748.4(ALDH4A1):c.453+1G>A	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574765	NM_003748.4(ALDH4A1):c.356del (p.Lys119fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574770	NM_003748.4(ALDH4A1):c.250-2A>G	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3574776	NM_003748.4(ALDH4A1):c.19_34dup (p.Leu12fs)	ALDH4A1	Likely pathogenic	criteria provided, single submitter
3655571	NM_003748.4(ALDH4A1):c.1461-2A>G	ALDH4A1	Likely pathogenic	criteria provided, single submitter
4004	NM_003748.4(ALDH4A1):c.21del (p.Leu8fs)	ALDH4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
571282	NM_003748.4(ALDH4A1):c.298-1G>C	ALDH4A1	Likely pathogenic	criteria provided, single submitter
1507387	NM_003748.4(ALDH4A1):c.361A>G (p.Ile121Val)	ALDH4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2878184	NM_003748.4(ALDH4A1):c.1A>G (p.Met1Val)	ALDH4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294370	NM_003748.4(ALDH4A1):c.1377G>C (p.Pro459=)	ALDH4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294372	NM_003748.4(ALDH4A1):c.1261T>C (p.Cys421Arg)	ALDH4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294378	NM_003748.4(ALDH4A1):c.1098G>A (p.Gly366=)	ALDH4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294379	NM_003748.4(ALDH4A1):c.1086G>C (p.Pro362=)	ALDH4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ALDH4A1	Definitive	Autosomal recessive	hyperprolinemia type 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH4A1	Orphanet:79101	Hyperprolinemia type 2

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
ALDH4A1	HGNC:406	ENSG00000159423	P30038	Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial	gencc,clinvar
AKR7A2	HGNC:389	ENSG00000053371	O43488	Aflatoxin B1 aldehyde reductase member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH4A1	Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial	Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate.
AKR7A2	Aflatoxin B1 aldehyde reductase member 2	Catalyzes the NADPH-dependent reduction of succinic semialdehyde to gamma-hydroxybutyrate.

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)
ALDH4A1	Enzyme (other)	yes	1.2.1.88	P5CDH/ALDH4A1, Aldehyde_DH_dom, Ald_DH_CS_CYS
AKR7A2	Other/Unknown	no		NADP_OxRdtase_dom, NAD(P)_OxRdtase_dom_sf, AKR_Detox_Biosynth

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
adult mammalian kidney	1
liver	1
right lobe of liver	1
duodenum	1
mucosa of transverse colon	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH4A1	248	ubiquitous	marker	right lobe of liver, liver, adult mammalian kidney
AKR7A2	283	ubiquitous	marker	mucosa of transverse colon, duodenum, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH4A1	3,623
AKR7A2	1,880

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH4A1	P30038	6
AKR7A2	O43488	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Proline catabolism	1	1903.3×	0.003	ALDH4A1
Glyoxylate metabolism and glycine degradation	1	380.7×	0.006	ALDH4A1
Aflatoxin activation and detoxification	1	317.2×	0.006	AKR7A2
Metabolism	2	11.6×	0.011	ALDH4A1, AKR7A2
Biological oxidations	1	64.9×	0.018	AKR7A2
Metabolism of amino acids and derivatives	1	33.8×	0.029	ALDH4A1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-proline metabolic process	1	2808.7×	0.001	ALDH4A1
obsolete L-proline catabolic process to L-glutamate	1	2808.7×	0.001	ALDH4A1
L-proline catabolic process	1	2106.5×	0.001	ALDH4A1
trans-4-hydroxy-L-proline catabolic process	1	1685.2×	0.001	ALDH4A1
daunorubicin metabolic process	1	766.0×	0.002	AKR7A2
aldehyde metabolic process	1	648.1×	0.002	AKR7A2
doxorubicin metabolic process	1	648.1×	0.002	AKR7A2
carbohydrate metabolic process	1	68.0×	0.016	AKR7A2
lipid metabolic process	1	45.8×	0.022	AKR7A2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 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
ALDH4A1	0	0
AKR7A2	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
ALDH4A1	1	Binding:1
AKR7A2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH4A1	1.2.1.88	L-glutamate gamma-semialdehyde dehydrogenase

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

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	1	ALDH4A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AKR7A2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDH4A1	1	—
AKR7A2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.