combined PSAP deficiency

Summary

combined PSAP deficiency (MONDO:0012719) is a disease caused by PSAP (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PSAP (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 108
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0001336	Myoclonus	Very frequent (80-99%)
HP:0001522	Death in infancy	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0002069	Bilateral tonic-clonic seizure	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined PSAP deficiency
Mondo ID	MONDO:0012719
MeSH	C567125
OMIM	611721
Orphanet	139406
DOID	DOID:0111330
SNOMED CT	720864008
UMLS	C2673635
MedGen	382151
GARD	0012505
Is cancer (heuristic)	no

Also known as: combined prosaposin deficiency · combined SAP deficiency · combined saposin deficiency · encephalopathy due to prosaposin deficiency · PSAPD

Data availability: 108 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 › inherited lipid metabolism disorder › lysosomal lipid storage disorder › sphingolipidosis › PSAP-related sphingolipidosis › combined PSAP deficiency

Related subtypes (3): metachromatic leukodystrophy due to saposin B deficiency, Gaucher disease due to saposin C deficiency, Krabbe disease due to saposin A 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

108 retrieved; paginated sample, class counts are floors:

34 conflicting classifications of pathogenicity, 32 uncertain significance, 11 benign, 11 likely pathogenic, 9 benign/likely benign, 6 pathogenic/likely pathogenic, 4 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1330309	NM_002778.4(PSAP):c.1005+1G>A	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13361	NM_002778.4(PSAP):c.650C>T (p.Thr217Ile)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13363	NM_002778.4(PSAP):c.722G>C (p.Cys241Ser)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13365	NM_002778.4(PSAP):c.1A>T (p.Met1Leu)	PSAP	Pathogenic	criteria provided, multiple submitters, no conflicts
13368	NM_002778.4(PSAP):c.794del (p.Cys265fs)	PSAP	Pathogenic	no assertion criteria provided
13375	NM_002778.4(PSAP):c.828_829del (p.Glu276fs)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582396	NM_002778.4(PSAP):c.1192+1G>A	PSAP	Pathogenic	criteria provided, single submitter
2735420	NM_002778.4(PSAP):c.148C>T (p.Gln50Ter)	PSAP	Pathogenic	criteria provided, multiple submitters, no conflicts
562226	NM_002778.4(PSAP):c.679_681del (p.Lys227del)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
857581	NM_002778.4(PSAP):c.645C>A (p.Asn215Lys)	PSAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687743	NM_002778.4(PSAP):c.1341C>A (p.Tyr447Ter)	CDH23	Likely pathogenic	criteria provided, single submitter
1184598	NM_002778.4(PSAP):c.1006-8_1021del	PSAP	Likely pathogenic	no assertion criteria provided
1184599	NM_002778.4(PSAP):c.698T>G (p.Leu233Arg)	PSAP	Likely pathogenic	no assertion criteria provided
13373	NM_002778.4(PSAP):c.1006-2A>G	PSAP	Likely pathogenic	criteria provided, single submitter
3597220	NM_002778.4(PSAP):c.1351-1G>T	PSAP	Likely pathogenic	criteria provided, single submitter
3597238	NM_002778.4(PSAP):c.1006-2_1017delinsT	PSAP	Likely pathogenic	criteria provided, single submitter
3597241	NM_002778.4(PSAP):c.1006-1G>A	PSAP	Likely pathogenic	criteria provided, single submitter
3597242	NM_002778.4(PSAP):c.1005+1G>T	PSAP	Likely pathogenic	criteria provided, single submitter
3597257	NM_002778.4(PSAP):c.568C>T (p.Gln190Ter)	PSAP	Likely pathogenic	criteria provided, single submitter
3768793	NC_000010.10:g.(73585651_73587770)_(73594263_73610938)dup	PSAP	Likely pathogenic	criteria provided, single submitter
438801	NM_002778.4(PSAP):c.1369G>T (p.Glu457Ter)	PSAP	Likely pathogenic	criteria provided, single submitter
300491	NM_022124.6(CDH23):c.*430A>T	CDH23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300492	NM_022124.6(CDH23):c.*434G>A	CDH23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
258805	NM_002778.4(PSAP):c.-28A>C	PSAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300503	NM_002778.4(PSAP):c.*122C>G	PSAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300506	NM_002778.4(PSAP):c.*9A>G	PSAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300507	NM_002778.4(PSAP):c.1476T>C (p.Thr492=)	PSAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300508	NM_002778.4(PSAP):c.1456C>T (p.His486Tyr)	PSAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300510	NM_002778.4(PSAP):c.1432-4A>G	PSAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300511	NM_002778.4(PSAP):c.1278C>T (p.Asn426=)	PSAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 36 · Orphanet: 12 · 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
MTCH1	Strong	Autosomal recessive	combined PSAP deficiency	18
PSAP	Strong	Autosomal recessive	combined PSAP deficiency	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSAP	Orphanet:139406	Encephalopathy due to prosaposin deficiency
PSAP	Orphanet:206436	Infantile Krabbe disease
PSAP	Orphanet:309252	Atypical Gaucher disease due to saposin C deficiency
PSAP	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
PSAP	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
PSAP	Orphanet:309271	Metachromatic leukodystrophy, adult form
CDH23	Orphanet:231169	Usher syndrome type 1
CDH23	Orphanet:2965	Prolactinoma
CDH23	Orphanet:314777	Familial isolated pituitary adenoma
CDH23	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:91347	TSH-secreting pituitary adenoma
CDH23	Orphanet:96253	Cushing disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTCH1	HGNC:17586	ENSG00000137409	Q9NZJ7	Mitochondrial carrier homolog 1	gencc,clinvar
PSAP	HGNC:9498	ENSG00000197746	P07602	Prosaposin	gencc,clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTCH1	Mitochondrial carrier homolog 1	Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane.
PSAP	Prosaposin	Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46).
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTCH1	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf
PSAP	Other/Unknown	no		SAP_A, SapB_1, SapB_2
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS

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
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
leukocyte	1
monocyte	1
mononuclear cell	1
left ovary	1
right ovary	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTCH1	288	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
PSAP	295	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH23	1,575
MTCH1	1,570
PSAP	217

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSAP	P07602	20
CDH23	Q9H251	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTCH1	Q9NZJ7	76.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 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
Sensory processing of sound	1	154.3×	0.040	CDH23
Glycosphingolipid metabolism	1	150.3×	0.040	PSAP
Glycosphingolipid catabolism	1	146.4×	0.040	PSAP
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.040	CDH23
Sphingolipid metabolism	1	84.0×	0.040	PSAP
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.040	PSAP
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.040	CDH23
Platelet activation, signaling and aggregation	1	52.9×	0.051	PSAP
Sensory Perception	1	47.6×	0.051	CDH23
Platelet degranulation	1	43.9×	0.051	PSAP
Class A/1 (Rhodopsin-like receptors)	1	37.1×	0.051	PSAP
Peptide ligand-binding receptors	1	37.1×	0.051	PSAP
GPCR ligand binding	1	32.1×	0.055	PSAP
GPCR downstream signalling	1	21.7×	0.073	PSAP
Signaling by GPCR	1	20.0×	0.073	PSAP
G alpha (i) signalling events	1	19.5×	0.073	PSAP
Hemostasis	1	18.0×	0.074	PSAP
Metabolism of lipids	1	15.8×	0.080	PSAP
Innate Immune System	1	12.8×	0.093	PSAP
Neutrophil degranulation	1	11.5×	0.098	PSAP
Immune System	1	6.5×	0.162	PSAP
Metabolism	1	5.8×	0.172	PSAP
Signal Transduction	1	5.1×	0.187	PSAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ganglioside GM1 transport to membrane	1	5617.3×	0.005	PSAP
neuronal ion channel clustering	1	1872.4×	0.008	MTCH1
epithelial cell differentiation involved in prostate gland development	1	1123.5×	0.008	PSAP
equilibrioception	1	802.5×	0.008	CDH23
prostate gland growth	1	702.2×	0.008	PSAP
sensory perception of light stimulus	1	624.1×	0.008	CDH23
protein insertion into mitochondrial outer membrane	1	432.1×	0.010	MTCH1
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	374.5×	0.010	CDH23
sphingolipid metabolic process	1	330.4×	0.010	PSAP
auditory receptor cell stereocilium organization	1	280.9×	0.010	CDH23
lysosomal transport	1	234.1×	0.011	PSAP
calcium-dependent cell-cell adhesion	1	160.5×	0.014	CDH23
cochlea development	1	156.0×	0.014	CDH23
regulation of lipid metabolic process	1	144.0×	0.014	PSAP
regulation of cytosolic calcium ion concentration	1	127.7×	0.015	CDH23
photoreceptor cell maintenance	1	119.5×	0.015	CDH23
regulation of signal transduction	1	89.2×	0.019	MTCH1
regulation of autophagy	1	80.2×	0.020	PSAP
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	73.0×	0.021	PSAP
calcium ion transport	1	60.4×	0.023	CDH23
locomotory behavior	1	59.8×	0.023	CDH23
homophilic cell-cell adhesion	1	46.8×	0.028	CDH23
neuron projection development	1	40.7×	0.031	CDH23
sensory perception of sound	1	33.6×	0.036	CDH23
gene expression	1	26.6×	0.042	PSAP
visual perception	1	26.5×	0.042	CDH23
cell migration	1	20.5×	0.052	CDH23
positive regulation of apoptotic process	1	18.9×	0.054	MTCH1
apoptotic process	1	9.6×	0.101	MTCH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSAP	1	3
MTCH1	0	0
CDH23	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FENRETINIDE	3	PSAP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSAP	12	Binding:8, ADMET:4

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

1 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)
FENRETINIDE	3	PSAP

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	1	PSAP
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MTCH1, CDH23

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)
MTCH1	0	—
CDH23	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.