Prolidase deficiency

Summary

Prolidase deficiency (MONDO:0008221) is a disease caused by PEPD (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PEPD (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 107
• Phenotypes (HPO): 39
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		90	Worldwide	Validated
Prevalence at birth	<1 / 1 000 000	0.08	Canada	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000370	Abnormality of the middle ear	Very frequent (80-99%)
HP:0000670	Carious teeth	Very frequent (80-99%)
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0000963	Thin skin	Very frequent (80-99%)
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0000992	Cutaneous photosensitivity	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002715	Abnormality of the immune system	Very frequent (80-99%)
HP:0003272	Abnormality of the hip bone	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0007473	Crusting erythematous dermatitis	Very frequent (80-99%)
HP:0008065	Aplasia/Hypoplasia of the skin	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0200042	Skin ulcer	Very frequent (80-99%)
HP:0000294	Low anterior hairline	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0001007	Hirsutism	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001231	Abnormal fingernail morphology	Frequent (30-79%)
HP:0002211	White forelock	Frequent (30-79%)
HP:0002230	Generalized hirsutism	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0007598	Bilateral single transverse palmar creases	Frequent (30-79%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0004349	Reduced bone mineral density	Occasional (5-29%)
HP:0010669	Hypoplasia of the zygomatic bone	Occasional (5-29%)
HP:0012786	Recurrent cystitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	prolidase deficiency
Mondo ID	MONDO:0008221
MeSH	D056732
OMIM	170100
Orphanet	742
DOID	DOID:0111540
ICD-11	1416203271
NCIT	C85029
SNOMED CT	410055005
UMLS	C0268532
MedGen	120647
GARD	0007473
Is cancer (heuristic)	no

Also known as: hyperimidodipeptiduria · Imidodipeptidase deficiency · Peptidase deficiency · prolidase deficiency

Data availability: 107 ClinVar variants · 4 GenCC gene-disease records · 8 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 › disorder of peptide and amine metabolism › inborn disorder of peptide metabolism › prolidase deficiency

Related subtypes (2): homocarnosinosis, late-onset nephronophthisis

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:

35 uncertain significance, 24 conflicting classifications of pathogenicity, 14 pathogenic, 10 pathogenic/likely pathogenic, 9 benign/likely benign, 8 benign, 4 likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299535	NM_000285.4(PEPD):c.2T>G (p.Met1Arg)	PEPD	Pathogenic	criteria provided, multiple submitters, no conflicts
1299536	NM_000285.4(PEPD):c.549-1G>T	PEPD	Pathogenic	criteria provided, single submitter
1324875	NM_000285.4(PEPD):c.418A>T (p.Lys140Ter)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1327989	NM_000285.4(PEPD):c.825del (p.Phe275fs)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414673	NM_000285.4(PEPD):c.2T>C (p.Met1Thr)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1440927	NM_000285.4(PEPD):c.550C>T (p.Arg184Ter)	PEPD	Pathogenic	criteria provided, multiple submitters, no conflicts
208	NM_000285.4(PEPD):c.826G>A (p.Asp276Asn)	PEPD	Pathogenic	criteria provided, multiple submitters, no conflicts
209	NM_000285.3(PEPD):c.1153_1344del (p.Gly385_Gly448del)	PEPD	Pathogenic	no assertion criteria provided
209997	NM_000285.4(PEPD):c.634G>C (p.Ala212Pro)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209998	NM_000285.4(PEPD):c.1103T>G (p.Leu368Arg)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211	NM_000285.4(PEPD):c.551G>A (p.Arg184Gln)	PEPD	Pathogenic	criteria provided, single submitter
212	NM_000285.4(PEPD):c.833G>A (p.Gly278Asp)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213	NM_000285.4(PEPD):c.1342G>A (p.Gly448Arg)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215	NM_000285.4(PEPD):c.793C>T (p.Arg265Ter)	PEPD	Pathogenic	criteria provided, multiple submitters, no conflicts
216	NM_000285.4(PEPD):c.1234G>A (p.Glu412Lys)	PEPD	Pathogenic	no assertion criteria provided
217	NM_000285.4(PEPD):c.611_623dup (p.Glu208_Val209insGlyProProTer)	PEPD	Pathogenic	criteria provided, single submitter
218	NM_000285.4(PEPD):c.605C>T (p.Ser202Phe)	PEPD	Pathogenic	no assertion criteria provided
2754795	NM_000285.4(PEPD):c.442-1G>C	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
328810	NM_000285.4(PEPD):c.692_694del (p.Tyr231del)	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583632	NM_000285.4(PEPD):c.768C>G (p.Tyr256Ter)	PEPD	Pathogenic	criteria provided, single submitter
620168	NM_000285.4(PEPD):c.977G>A (p.Trp326Ter)	PEPD	Pathogenic	criteria provided, multiple submitters, no conflicts
804428	NM_000285.4(PEPD):c.504-1G>A	PEPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807649	NM_000285.4(PEPD):c.549-1G>A	PEPD	Pathogenic	criteria provided, multiple submitters, no conflicts
807650	NM_000285.4(PEPD):c.540del (p.Ile180fs)	PEPD	Pathogenic	criteria provided, single submitter
1485637	NM_000285.4(PEPD):c.819-1G>A	PEPD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583630	NM_000285.4(PEPD):c.1152+1G>A	PEPD	Likely pathogenic	criteria provided, single submitter
3583633	NM_000285.4(PEPD):c.504-2A>C	PEPD	Likely pathogenic	criteria provided, single submitter
3583634	NM_000285.4(PEPD):c.146_149delinsGGGGA (p.Gln49fs)	PEPD	Likely pathogenic	criteria provided, single submitter
328786	NM_000285.4(PEPD):c.1345-11G>C	PEPD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328789	NM_000285.4(PEPD):c.1311C>T (p.Arg437=)	PEPD	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
PEPD	Definitive	Autosomal recessive	prolidase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEPD	Orphanet:742	Prolidase 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
PEPD	HGNC:8840	ENSG00000124299	P12955	Xaa-Pro dipeptidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEPD	Xaa-Pro dipeptidase	Dipeptidase that catalyzes the hydrolysis of dipeptides with a prolyl (Xaa-Pro) or hydroxyprolyl residue in the C-terminal position.

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEPD	Protease	yes	3.4.13.9	Pept_M24, Peptidase_M24B_aminopep-P_CS, Aminopep_P_N

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
adult mammalian kidney	1
ileal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEPD	276	ubiquitous	marker	ileal mucosa, adult mammalian kidney, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEPD	2,471

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PEPD	P12955	21

Function

Pathway analysis

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

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
amino acid metabolic process	1	802.5×	0.003	PEPD
negative regulation of programmed cell death	1	732.7×	0.003	PEPD
collagen catabolic process	1	391.9×	0.003	PEPD
proteolysis	1	34.2×	0.029	PEPD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
PEPD	CAPTOPRIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PEPD	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPTOPRIL	4	PEPD
DAUNORUBICIN	4	PEPD
DOXORUBICIN	4	PEPD
GENTAMICIN	4	PEPD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PEPD	31	Binding:31

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PEPD	3.4.13.9	Xaa-Pro dipeptidase

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

4 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)
CAPTOPRIL	4	PEPD
DAUNORUBICIN	4	PEPD
DOXORUBICIN	4	PEPD
GENTAMICIN	4	PEPD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PEPD
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	0

Undrugged target profiles

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

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
NCT03334968	Not specified	COMPLETED	Prolidase Enzyme Activity in Stroke Patients