Is PSAP p.Tyr2Phe (c.5A>T) pathogenic?

PSAP p.Tyr2Phe (c.5A>T) is classified Uncertain significance in PSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely benign (0.0688); Absent from gnomAD v4.1; Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Tyr2Phe (c.5A>T)?

PSAP p.Tyr2Phe (c.5A>T) is associated with metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Tyr2Phe (c.5A>T) in the general population?

PSAP p.Tyr2Phe (c.5A>T) is absent from gnomAD v4.1 (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

What do computational predictors say about PSAP p.Tyr2Phe (c.5A>T)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

PSAP p.Tyr2Phe

c.5A>T · rs759590269 · VCV1518948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.46, phastCons 0.34
Overall
CADD	12.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PSAP
Protein: p.Tyr2Phe
Coding: c.5A>T
MANE Select: NM_002778
dbSNP: rs759590269
Type: single nucleotide variant
Location: chr10:71851217 (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

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.Tyr2= Likely benign ★★ 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-tyr2phe (accessed [today's date]).

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