Is PSAP p.Cys42= (c.126C>T) pathogenic?

PSAP p.Cys42= (c.126C>T) is classified Likely benign in PSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). Very rare (popmax 0.00668%, eas); Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Cys42= (c.126C>T)?

PSAP p.Cys42= (c.126C>T) is associated with metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Cys42= (c.126C>T) in the general population?

PSAP p.Cys42= (c.126C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

PSAP p.Cys42=

c.126C>T · rs372943091 · VCV1614930

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

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 -6.4	GERP -3.6
Overall
CADD	0.411	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,888 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000867% 14/1,613,834 alleles · very rare exomes 13/1,461,616 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,963
South Asian	0.00549%	18,212
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000424%	236,000

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.Cys42=
Coding: c.126C>T
MANE Select: NM_002778
dbSNP: rs372943091
Type: single nucleotide variant
Location: chr10:71834420 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 42: the saposin a-type 1 domain

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.Cys42Tyr 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-cys42 (accessed [today's date]).

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