Is PSAP p.Ser441= (c.1323C>T) pathogenic?

PSAP p.Ser441= (c.1323C>T) is classified Likely benign in PSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). Very rare (popmax 8.47e-05%, nfe); Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Ser441= (c.1323C>T)?

PSAP p.Ser441= (c.1323C>T) is associated with metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Ser441= (c.1323C>T) in the general population?

PSAP p.Ser441= (c.1323C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

PSAP p.Ser441=

c.1323C>T · rs1419823465 · VCV1138420

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

metachromatic leukodystrophy due to saposin B 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 5.1	GERP 1.9, phastCons 1
Overall
CADD	11.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,058 alleles

Overall 0.000248% 4/1,614,112 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)grpmax	8.47e-05%	1,180,058

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Ser441=
Coding: c.1323C>T
MANE Select: NM_002778
dbSNP: rs1419823465
Type: single nucleotide variant
Location: chr10:71819492 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 441: the saposin b-type 4 domain; an α-helix

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

Disease context

metachromatic leukodystrophy due to saposin B deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Metachromatic leukodystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PSAP p.Ser441Arg Uncertain significance ★★ ⚠ same residue
PSAP p.Ser441Asn 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

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-ser441 (accessed [today's date]).

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