Hyperprolinemia type 1

Summary

Hyperprolinemia type 1 (MONDO:0009400) is a disease caused by PRODH (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PRODH (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 397
• Phenotypes (HPO): 6

Clinical features

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000112	Nephropathy	Frequent (30-79%)
HP:0003137	Prolinuria	Frequent (30-79%)
HP:0008358	Hyperprolinemia	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperprolinemia type 1
Mondo ID	MONDO:0009400
OMIM	239500
Orphanet	419
DOID	DOID:0080542
SNOMED CT	61071003
UMLS	C0268529
MedGen	120645
GARD	0024670
MedDRA	10058513
Is cancer (heuristic)	no

Also known as: HPI · hyperprolinemia caused by mutation in PRODH · hyperprolinemia type 1 · hyperprolinemia, type I · HYRPRO1 · PRODH hyperprolinemia · proline oxidase deficiency

Data availability: 397 ClinVar variants · 4 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 1

Related subtypes (1): hyperprolinemia type 2

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

397 retrieved; paginated sample, class counts are floors:

172 uncertain significance, 133 likely benign, 32 benign, 21 conflicting classifications of pathogenicity, 19 pathogenic, 10 benign/likely benign, 8 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
583475	NC_000022.11:g.(?18906375)(18986158_?)del	DGCR5	Pathogenic	criteria provided, single submitter
1072697	NC_000022.10:g.(?18899287)(18925066_?)del	DGCR6	Pathogenic	criteria provided, single submitter
4005	NC_000022.11:g.(?18906222)(18936553_?)del	DGCR6	Pathogenic; risk factor	no assertion criteria provided
459905	NC_000022.11:g.(?18913155)(18936307_?)del	HSERVPRODH	Pathogenic	criteria provided, single submitter
459906	NC_000022.11:g.(?18922797)(18936307_?)del	HSERVPRODH	Pathogenic	criteria provided, single submitter
1179113	GRCh37/hg19 22q11.21(chr22:18900294-18923806)	PRODH	Pathogenic	no assertion criteria provided
1399310	NM_016335.6(PRODH):c.236T>A (p.Leu79Ter)	PRODH	Pathogenic	criteria provided, single submitter
1425627	NM_016335.6(PRODH):c.522_526dup (p.Lys176fs)	PRODH	Pathogenic	criteria provided, single submitter
1457425	NC_000022.10:g.(?18910310)(18923800_?)del	PRODH	Pathogenic	criteria provided, single submitter
1974075	NM_016335.6(PRODH):c.543C>A (p.Tyr181Ter)	PRODH	Pathogenic	criteria provided, single submitter
1998253	NM_016335.6(PRODH):c.969_972del (p.Ser323fs)	PRODH	Pathogenic	criteria provided, single submitter
2021179	NM_016335.6(PRODH):c.323del (p.Leu108fs)	PRODH	Pathogenic	criteria provided, single submitter
2134144	NM_016335.6(PRODH):c.379C>T (p.Gln127Ter)	PRODH	Pathogenic	criteria provided, single submitter
2166769	NM_016335.6(PRODH):c.38dup (p.Cys13fs)	PRODH	Pathogenic	criteria provided, single submitter
2167860	NM_016335.6(PRODH):c.457del (p.Glu153fs)	PRODH	Pathogenic	criteria provided, single submitter
2682549	NC_000022.10:g.(?18900293)(18923807_?)del	PRODH	Pathogenic	criteria provided, single submitter
2916786	NM_016335.6(PRODH):c.175C>T (p.Gln59Ter)	PRODH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3247249	NC_000022.10:g.(?18900688)(18923800_?)del	PRODH	Pathogenic	criteria provided, single submitter
3708754	NM_016335.6(PRODH):c.1094del (p.Val365fs)	PRODH	Pathogenic	criteria provided, single submitter
4012	NM_016335.6(PRODH):c.1561C>G (p.Arg521Gly)	PRODH	Pathogenic	no assertion criteria provided
521785	NM_016335.6(PRODH):c.1236C>A (p.Tyr412Ter)	PRODH	Pathogenic	criteria provided, multiple submitters, no conflicts
1179165	GRCh37/hg19 22q11.21(chr22:18900895-18923882)	PRODH	Likely pathogenic	no assertion criteria provided
2201654	NM_016335.6(PRODH):c.1104+2T>C	PRODH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587798	NM_016335.6(PRODH):c.1252-1G>A	PRODH	Likely pathogenic	criteria provided, single submitter
3587800	NM_016335.6(PRODH):c.1251+2C>T	PRODH	Likely pathogenic	criteria provided, single submitter
3587804	NM_016335.6(PRODH):c.1177_1183del (p.Leu393fs)	PRODH	Likely pathogenic	criteria provided, single submitter
3587838	NM_016335.6(PRODH):c.148_157del (p.Val50fs)	PRODH	Likely pathogenic	criteria provided, single submitter
3587846	NM_016335.6(PRODH):c.2T>G (p.Met1Arg)	PRODH	Likely pathogenic	criteria provided, single submitter
3587847	NM_016335.6(PRODH):c.1A>C (p.Met1Leu)	PRODH	Likely pathogenic	criteria provided, single submitter
1214571	NM_016335.6(PRODH):c.1729C>T (p.Arg577Trp)	PRODH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PRODH	Definitive	Autosomal recessive	hyperprolinemia type 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRODH	Orphanet:419	Hyperprolinemia type 1

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRODH	HGNC:9453	ENSG00000100033	O43272	Proline dehydrogenase 1, mitochondrial	gencc,clinvar
DGCR5	HGNC:16757	ENSG00000273032		DiGeorge syndrome critical region gene 5	clinvar
DGCR6	HGNC:2846	ENSG00000183628	Q14129	Protein DGCR6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRODH	Proline dehydrogenase 1, mitochondrial	Converts proline to delta-1-pyrroline-5-carboxylate.
DGCR6	Protein DGCR6	May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRODH	Enzyme (other)	yes	1.5.5.2	Proline_DH_dom, Proline_oxidase, FAD-linked_oxidoreductase-like
DGCR5	Other/Unknown	no
DGCR6	Other/Unknown	no		Gonadal

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
skin of leg	1
zone of skin	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRODH	135	broad	marker	skin of leg, zone of skin, skin of abdomen
DGCR5	183	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
DGCR6	134	ubiquitous	marker	skeletal muscle tissue, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRODH	3,653
DGCR6	581
DGCR5	0

Intra-cohort edges

A	B	Sources
DGCR6	PRODH	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DGCR6	Q14129	86.83
PRODH	O43272	85.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
Proline catabolism	1	3806.7×	3e-04	PRODH

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×	9e-04	PRODH
obsolete L-proline catabolic process to L-glutamate	1	2808.7×	9e-04	PRODH
L-proline catabolic process	1	2106.5×	9e-04	PRODH
trans-4-hydroxy-L-proline catabolic process	1	1685.2×	9e-04	PRODH
regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	1685.2×	9e-04	PRODH
intrinsic apoptotic signaling pathway in response to oxidative stress	1	421.3×	0.003	PRODH
animal organ morphogenesis	1	95.8×	0.012	DGCR6
cell adhesion	1	18.7×	0.053	DGCR6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
PRODH	0	0
DGCR5	0	0
DGCR6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRODH	1.5.5.2, 1.5.99.B2	proline dehydrogenase,

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	PRODH
E	Difficult family or no structure, no drug	2	DGCR5, DGCR6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRODH	0	—
DGCR5	0	—
DGCR6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.