PSAP

Chr 10ADAR

prosaposin

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

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]

GeneReviewsOMIMResearchGenerating clinical summary…
LOFmechanismAD/ARLOEUF 0.285 OMIM phenotypes
Clinical SummaryPSAP
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Gene-Disease Validity (ClinGen)
metachromatic leukodystrophy due to saposin B deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

4 total gene-disease associations curated

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
102 unique Pathogenic / Likely Pathogenic· 300 VUS of 1008 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
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GeneReview available — PSAP
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint?
0.28LOEUF
pLI 0.991
Z-score 4.30
OE 0.11 (0.050.28)
Highly constrained

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

Missense Constraint?
-0.52Z-score
OE missense 1.09 (0.991.19)
314 obs / 288.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?
LoF OE?0.11 (0.050.28)
00.351.4
Missense OE?1.09 (0.991.19)
00.61.4
Synonymous OE?1.16
01.21.6
LoF obs/exp: 3 / 27.2Missense obs/exp: 314 / 288.9Syn Z: -1.34
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitivePSAP-related atypical Krabbe diseaseLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.5476th %ile
GOF
0.6737th %ile
LOF
0.4726th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

1008 submitted variants in ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic60
VUS300
Likely Benign487
Benign49
Conflicting47
42
Pathogenic
60
Likely Pathogenic
300
VUS
487
Likely Benign
49
Benign
47
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
7
4
0
42
Likely Pathogenic
43
13
3
1
60
VUS
1
253
36
10
300
Likely Benign
0
8
231
248
487
Benign
0
1
46
2
49
Conflicting
47
Total75282320261985

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

13 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap PSAP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

PSAP · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.