Is PSAP p.Cys63= (c.189C>T) pathogenic?

PSAP p.Cys63= (c.189C>T) is classified Conflicting classifications of pathogenicity in PSAP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Rare (popmax 0.501%, nfe); Associated with Krabbe disease due to saposin A deficiency.

What condition is associated with PSAP p.Cys63= (c.189C>T)?

PSAP p.Cys63= (c.189C>T) is associated with Krabbe disease due to saposin A deficiency, metachromatic leukodystrophy due to saposin B deficiency, Gaucher disease due to saposin C deficiency (ClinVar).

How common is PSAP p.Cys63= (c.189C>T) in the general population?

PSAP p.Cys63= (c.189C>T) is rare (popmax 0.501%, nfe) (gnomAD).

PSAP p.Cys63=

c.189C>T · rs111369573 · VCV300531

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.501%, nfe)

Conditions

Krabbe disease due to saposin A deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.1	GERP -3.2
Overall
CADD	0.806	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.501% European (non-Finnish) · 5,910/1,179,886 alleles

Filtering AF 0.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.486%

Overall 0.393% 6,344/1,613,890 alleles · rare exomes 5,969/1,461,640 · genomes 375/152,250 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.501%	200
Remaining individualsnot grpmax-eligible	0.235%	425
Finnishnot grpmax-eligible	0.158%	633
African / African-American	0.092%	1,087
Admixed American	0.0817%	1,225
South Asian	0.0703%	1,423
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,402

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.Cys63=
Coding: c.189C>T
MANE Select: NM_002778
dbSNP: rs111369573
Type: single nucleotide variant
Location: chr10:71831906 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 63: the saposin b-type 1 domain; a disulfide bond; an α-helix

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

Disease context

Krabbe disease due to saposin A 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 combined PSAP deficiency

Similar variants

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
PSAP p.Cys241Ser 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-cys63 (accessed [today's date]).

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