Is PSAP p.Pro189Ser (c.565C>T) pathogenic?

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.

What condition is associated with PSAP p.Pro189Ser (c.565C>T)?

PSAP p.Pro189Ser (c.565C>T) is associated with combined PSAP deficiency, metachromatic leukodystrophy due to saposin B deficiency, Gaucher disease due to saposin C deficiency (ClinVar).

How common is PSAP p.Pro189Ser (c.565C>T) in the general population?

PSAP p.Pro189Ser (c.565C>T) is rare (popmax 0.198%, eas) (gnomAD).

How is Encephalopathy due to prosaposin deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PSAP p.Pro189Ser (c.565C>T)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

PSAP p.Pro189Ser

c.565C>T · rs188854022 · VCV878037

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined PSAP deficiency

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.64, phastCons 1
Overall
CADD	17.93	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.198% East Asian · 89/44,874 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.153%

Overall 0.00663% 107/1,614,040 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.198%	504
South Asian	0.0176%	5,692
Remaining individualsnot grpmax-eligible	0.0032%	31,246

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PSAP
Protein: p.Pro189Ser
Coding: c.565C>T
MANE Select: NM_002778
dbSNP: rs188854022
Type: single nucleotide variant
Location: chr10:71828888 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB

Full PSAP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined PSAP deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: metachromatic leukodystrophy due to saposin B deficiency Gaucher disease due to saposin C deficiency Krabbe disease due to saposin A deficiency

For Encephalopathy due to prosaposin deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PSAP p.Pro189= Likely benign ★ same residue
PSAP c.1005+1G>A Pathogenic/Likely pathogenic ★★ same condition
PSAP c.375+1G>T Likely pathogenic ★★ same condition
PSAP c.576+1G>A Likely pathogenic ★★ same condition
PSAP c.577-1G>T Pathogenic ★★ same condition
PSAP c.721-1G>A Likely pathogenic ★★ same condition
PSAP p.Asn215His Pathogenic/Likely pathogenic ★★ same condition
PSAP p.Asn215Lys Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/psap-p-pro189ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown