# NM_002778.4(PSAP):c.565C>T (p.Pro189Ser)

https://sugi.bio/variant/psap-p-pro189ser

## Summary

**PSAP p.Pro189Ser (c.565C>T)** is classified **Conflicting classifications of pathogenicity** in PSAP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.075); Rare (popmax 0.198%, eas); Associated with combined PSAP deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs188854022 · 4 submitters · 4 linked conditions · AlphaMissense likely benign · rare (popmax 0.198%, eas)

## For patients & families {#patients}

This is a change in the PSAP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to combined PSAP deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | PSAP is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Encephalopathy due to prosaposin deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of eye movement — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Dystonia — Very frequent (99-80%)
- Myoclonus — Very frequent (99-80%)
- Death in infancy — Very frequent (99-80%)
- Splenomegaly — Very frequent (99-80%)
- Bilateral tonic-clonic seizure — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012505/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PSAP](https://sugi.bio/atlas/gene/PSAP/) |
| Protein change (HGVS p.) | p.Pro189Ser |
| Coding change (HGVS c.) | c.565C>T |
| MANE Select transcript | [NM_002778](https://www.ncbi.nlm.nih.gov/nuccore/NM_002778) |
| dbSNP | [rs188854022](https://www.ncbi.nlm.nih.gov/snp/rs188854022/) |
| Variant type | single nucleotide variant |
| Location | chr10:71828888-71828888 (GRCh38) |
| ClinVar | [VCV878037](https://www.ncbi.nlm.nih.gov/clinvar/variation/878037/) |

**All HGVS expressions:** `NC_000010.10:g.73588645G>A`, `NC_000010.11:g.71828888G>A`, `NG_009301.1:g.27438C>T`, `NM_001042465.3:c.565C>T`, `NM_001042466.3:c.565C>T`, `NM_002778.3:c.565C>T`, `NM_002778.4:c.565C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.075)
- REVEL 0.047 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.87 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.871, GERP -0.637, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.93**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.198%** (eas) · FAF95 0.165% · FAF99 0.153% · 89/44,874 in the highest group · 107/1,614,040 alleles overall — rare (popmax 0.198%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.198% | 504 |
| South Asian | 0.0176% | 5,692 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,246 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PSAP** population constraint: LOEUF 0.507, pLI 0.95247, missense-Z 0.73992. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **metachromatic leukodystrophy due to saposin B deficiency** — Definitive (AR)
- **Krabbe disease due to saposin A deficiency** — Moderate (AR)
- **Gaucher disease due to saposin C deficiency** — Definitive (AR)
- **combined PSAP deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.90, 17% of residues very-high.

**21 experimental structure(s)** (PDB): [1M12](https://www.rcsb.org/structure/1M12), [1N69](https://www.rcsb.org/structure/1N69), [1SN6](https://www.rcsb.org/structure/1SN6), [2DOB](https://www.rcsb.org/structure/2DOB), [2GTG](https://www.rcsb.org/structure/2GTG), [2QYP](https://www.rcsb.org/structure/2QYP) — incl. mutant structure 2R0R.

## What this gene does {#gene-function}

*Describes the biological roles of PSAP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PSAP's established molecular role includes protease binding.


### Pathways affected {#pathways}

PSAP participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, phospholipid binding, identical protein binding, protein homodimerization activity, scaffold protein binding, ganglioside GM1 binding.

**Biological process:** lysosomal transport, gene expression, ganglioside GM1 transport to membrane.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-30.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 7 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-30 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-23 |

## Associated conditions {#conditions}

[combined PSAP deficiency](https://sugi.bio/atlas/disease/combined-psap-deficiency/), [metachromatic leukodystrophy due to saposin B deficiency](https://sugi.bio/atlas/disease/metachromatic-leukodystrophy-due-to-saposin-b-deficiency/), [Gaucher disease due to saposin C deficiency](https://sugi.bio/atlas/disease/gaucher-disease-due-to-saposin-c-deficiency/), [Krabbe disease due to saposin A deficiency](https://sugi.bio/atlas/disease/krabbe-disease-due-to-saposin-a-deficiency/).

**Reported phenotype names (ClinVar):** Combined PSAP deficiency, Gaucher disease due to saposin C deficiency, Sphingolipid activator protein 1 deficiency, Krabbe disease due to saposin A deficiency, not specified, not provided, AllHighlyPenetrant, none provided, PROSAPOSIN DEFICIENCY, Encephalopathy due to prosaposin deficiency.

## Similar variants {#similar}

Related PSAP variant pages (same residue, condition, or type): [PSAP p.Pro189=](/variant/psap-p-pro189), [PSAP c.1005+1G>A](/variant/psap-c-1005-plus-1g-a), [PSAP c.375+1G>T](/variant/psap-c-375-plus-1g-t), [PSAP c.576+1G>A](/variant/psap-c-576-plus-1g-a), [PSAP c.577-1G>T](/variant/psap-c-577-minus-1g-t), [PSAP c.721-1G>A](/variant/psap-c-721-minus-1g-a), [PSAP p.Asn215His](/variant/psap-p-asn215his), [PSAP p.Asn215Lys](/variant/psap-p-asn215lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 878037). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*