Is PSAP p.Tyr2= (c.6C>T) pathogenic?

PSAP p.Tyr2= (c.6C>T) is classified Likely benign in PSAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). Very rare (popmax 0.00558%, nfe); Associated with metachromatic leukodystrophy due to saposin B deficiency.

How common is PSAP p.Tyr2= (c.6C>T) in the general population?

PSAP p.Tyr2= (c.6C>T) is very rare (popmax 0.00558%, nfe) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

PSAP p.Tyr2=

Q: What condition is associated with PSAP p.Tyr2= (c.6C>T)?

PSAP p.Tyr2= (c.6C>T) is associated with metachromatic leukodystrophy due to saposin B deficiency, metachromatic leukodystrophy (ClinVar).

c.6C>T · rs774482765 · VCV785881

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00558%, 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 -0.019	GERP -3
Overall
CADD	5.004	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00558% European (non-Finnish) · 64/1,146,868 alleles

Filtering AF 0.00447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00407%

Overall 0.00509% 79/1,551,010 alleles · very rare exomes 73/1,398,732 · genomes 6/152,278 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0168%	5,944
European (non-Finnish)grpmax	0.00558%	17,920
Admixed American	0.00392%	25,497
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,642
Remaining individualsnot grpmax-eligible	0.00166%	60,074
African / African-American	0.00137%	73,070

Finnish 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.Tyr2=
Coding: c.6C>T
MANE Select: NM_002778
dbSNP: rs774482765
Type: single nucleotide variant
Location: chr10:71851216 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB

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

PSAP p.Tyr2Cys Uncertain significance ★★ ⚠ same residue
PSAP p.Tyr2Phe 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-tyr2 (accessed [today's date]).

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