PSAP

Chr 10ADAR

prosaposin

Also known as: GLBA, PARK24, PSAPD, SAP1, SAP2

NCBI Gene: 5660 ENSG00000197746 UniProt: Q9NZJ7 OMIM: 176801

The protein is proteolytically processed to generate four saposins (A-D) that localize to lysosomes and facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. Mutations cause autosomal recessive lysosomal storage disorders including combined saposin deficiency, metachromatic leukodystrophy due to saposin B deficiency, and atypical forms of Gaucher and Krabbe diseases, as well as autosomal dominant susceptibility to Parkinson disease. The pathogenic mechanism involves impaired glycosphingolipid degradation due to deficient saposin cofactor function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a highly conserved preproprotein that is proteolytically processed to generate four main cleavage products including saposins A, B, C, and D. Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities. Mutations in this gene have been associated with Gaucher disease and metachromatic leukodystrophy. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Parkinson disease 24, susceptibility to}MIM #619491

Combined SAP deficiencyMIM #611721

Gaucher disease, atypicalMIM #610539

Krabbe disease, atypicalMIM #611722

Metachromatic leukodystrophy due to SAP-b deficiencyMIM #249900

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

108

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — PSAP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.991

Z-score 4.30

OE 0.11 (0.05–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

-0.52Z-score

OE missense 1.09 (0.99–1.19)

314 obs / 288.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.11 (0.05–0.28)

0≤0.351.4

Missense OE?1.09 (0.99–1.19)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 3 / 27.2Missense obs/exp: 314 / 288.9Syn Z: -1.34

Background carrier burden — how many people carry a rare variant somewhere in PSAP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

691 rare PASS variants

Rare truncating (LoF)

1 in 3,700

67 rare PASS variants

Rare synonymous (reference)

1 in 110

288 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PSAP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 96	1 in 2,700
South Asian	~43k	1 in 64	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 65	1 in 3,800
European (Finnish)	~27k	1 in 160	none seen
Admixed American	~22k	1 in 64	none seen
African / African American	~21k	1 in 89	1 in 3,300
East Asian	~20k	1 in 110	1 in 1,800
Ashkenazi Jewish	~13k	1 in 300	none seen
Middle Eastern	~2,884	1 in 71	≈ 1 in 2,200

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓