Is PSAP p.Tyr458= (c.1374C>T) pathogenic?

PSAP p.Tyr458= (c.1374C>T) is classified Likely benign in PSAP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0825%, mid); Associated with metachromatic leukodystrophy due to saposin B deficiency.

How common is PSAP p.Tyr458= (c.1374C>T) in the general population?

PSAP p.Tyr458= (c.1374C>T) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

PSAP p.Tyr458=

Q: What condition is associated with PSAP p.Tyr458= (c.1374C>T)?

PSAP p.Tyr458= (c.1374C>T) is associated with metachromatic leukodystrophy due to saposin B deficiency, metachromatic leukodystrophy (ClinVar).

c.1374C>T · rs146925179 · VCV724220

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

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 -1.7	GERP -4
Overall
CADD	1.289	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0355%

Overall 0.0322% 520/1,614,088 alleles · ultra-rare exomes 490/1,461,772 · genomes 30/152,316 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
European (non-Finnish)	0.0397%	2,521
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed American	0.0217%	4,618
African / African-American	0.016%	6,253
East Asian	0.00446%	22,444
South Asian	0.00329%	30,357
Finnishnot grpmax-eligible	0.00312%	32,008

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.Tyr458=
Coding: c.1374C>T
MANE Select: NM_002778
dbSNP: rs146925179
Type: single nucleotide variant
Location: chr10:71819088 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 458: 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

Also linked: metachromatic leukodystrophy

For Metachromatic leukodystrophy (Orphanet):

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

Similar variants

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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-tyr458 (accessed [today's date]).

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