PSAP

Chr 10ADAR

prosaposin

ENSG00000197746 UniProt: Q9NZJ7

Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane (PubMed:36264797). Catalyzes insertion of proteins with alpha-helical transmembrane regions, such as signal-anchored, tail-anchored and multi-pass membrane proteins (By similarity). Does not mediate insertion of beta-barrel transmembrane proteins (By similarity). May play a role in apoptosis (PubMed:12377771)

Primary Disease Associations & Inheritance

{Parkinson disease 24, autosomal dominant, susceptibility to}MIM #619491

Combined SAP deficiencyMIM #611721

Gaucher disease, atypicalMIM #610539

Krabbe disease, atypicalMIM #611722

Metachromatic leukodystrophy due to SAP-b deficiencyMIM #249900

500

ClinVar variants

Pathogenic / LP

0.99

pLI score· haploinsufficient

Active trials

Clinical Summary— PSAP

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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

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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

47 Pathogenic / Likely Pathogenic· 143 VUS of 500 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.52Z-score

OE missense 1.09 (0.99–1.19)

314 obs / 288.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.11 (0.05–0.28)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.09 (0.99–1.19)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.16

0≤1.21.6

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

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic20

VUS143

Likely Benign293

Benign3

Conflicting14

Pathogenic

Likely Pathogenic

143

VUS

293

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	2	13	0	27
Likely Pathogenic	13	4	3	0	20
VUS	0	118	21	4	143
Likely Benign	0	5	146	142	293
Benign	0	1	2	0	3
Conflicting	—				14
Total	25	130	185	146	500

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

View in ClinVar →

Protein Context — Lollipop Plot

PSAP · protein map & ClinVar variants

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

Gene2Phenotype Curations

PSAP-related atypical Krabbe disease

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

PROSAPOSIN; PSAP

MIM #176801 · *

{Parkinson disease 24, autosomal dominant, susceptibility to}

MIM #619491