# NM_002778.4(PSAP):c.53C>G (p.Pro18Arg)

https://sugi.bio/variant/psap-p-pro18arg

## Summary

**PSAP p.Pro18Arg (c.53C>G)** is classified **Uncertain significance** in PSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-28). AlphaMissense: likely benign (0.1913); Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the PSAP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Pro18Arg |
| Coding change (HGVS c.) | c.53C>G |
| MANE Select transcript | [NM_002778](https://www.ncbi.nlm.nih.gov/nuccore/NM_002778) |
| Variant type | single nucleotide variant |
| Location | chr10:71834493-71834493 (GRCh38) |
| ClinVar | [VCV4908002](https://www.ncbi.nlm.nih.gov/clinvar/variation/4908002/) |

**All HGVS expressions:** `NC_000010.10:g.73594250G>C`, `NC_000010.11:g.71834493G>C`, `NG_009301.1:g.21833C>G`, `NM_001042465.3:c.53C>G`, `NM_001042466.3:c.53C>G`, `NM_002778.4:c.53C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1913)
- REVEL 0.533 (indeterminate)
- SaProt LLR -9.894 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 11.807, GERP 1.79, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.8**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,942 in the highest group · 2/1,613,922 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,490 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,179,942 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **18** lies in the saposin a-type 1 domain.

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. p.Pro18Arg falls in the saposin a-type 1 domain.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-05-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-28 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PSAP variant pages (same residue, condition, or type): [PSAP p.Pro18Ala](/variant/psap-p-pro18ala), [PSAP p.Pro18Leu](/variant/psap-p-pro18leu), [PSAP p.Pro18=](/variant/psap-p-pro18), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4908002). 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.*