Is PSAP p.Cys409= (c.1227C>T) pathogenic?

PSAP p.Cys409= (c.1227C>T) is classified Likely benign in PSAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-24). Very rare (popmax 0.00769%, sas); Associated with Inborn genetic diseases.

What condition is associated with PSAP p.Cys409= (c.1227C>T)?

PSAP p.Cys409= (c.1227C>T) is associated with Inborn genetic diseases, metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Cys409= (c.1227C>T) in the general population?

PSAP p.Cys409= (c.1227C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

PSAP p.Cys409=

c.1227C>T · rs147030327 · VCV1148244

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Conditions

Inborn genetic diseases

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 -1.2	GERP -2.8
Overall
CADD	6.538	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,086 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00304% 49/1,614,180 alleles · very rare exomes 45/1,461,878 · genomes 4/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,012
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Admixed American	0.00333%	30,011
European (non-Finnish)	0.00288%	34,707
East Asian	0.00223%	44,882
African / African-American	0.00133%	75,042

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.Cys409=
Coding: c.1227C>T
MANE Select: NM_002778
dbSNP: rs147030327
Type: single nucleotide variant
Location: chr10:71819588 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 409: the saposin b-type 4 domain; a disulfide bond; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: metachromatic leukodystrophy due to saposin B deficiency

Similar variants

PSAP p.Cys409Trp Uncertain significance ★ ⚠ 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-cys409 (accessed [today's date]).

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