Is PSAP p.Leu10Phe (c.28C>T) pathogenic?

PSAP p.Leu10Phe (c.28C>T) is classified Uncertain significance in PSAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-11-03). AlphaMissense: likely benign (0.068); Ultra-rare (popmax 0.0369%, sas); Associated with metachromatic leukodystrophy due to saposin B deficiency.

How common is PSAP p.Leu10Phe (c.28C>T) in the general population?

PSAP p.Leu10Phe (c.28C>T) is ultra-rare (popmax 0.0369%, sas) (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.Leu10Phe (c.28C>T)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

PSAP p.Leu10Phe

Q: What condition is associated with PSAP p.Leu10Phe (c.28C>T)?

PSAP p.Leu10Phe (c.28C>T) is associated with metachromatic leukodystrophy due to saposin B deficiency, combined PSAP deficiency (ClinVar).

c.28C>T · rs779742363 · VCV806507

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0369%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -7.86	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 4.7	GERP -0.82, phastCons 1
Overall
CADD	16.92	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

Grpmax group 0.0369% South Asian · 31/84,068 alleles

Filtering AF 0.0266% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.00954% 148/1,551,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0369%	2,712
Middle Eastern	0.0167%	6,000
Remaining individualsnot grpmax-eligible	0.0133%	7,509
European (non-Finnish)	0.00916%	10,922
African / African-American	0.00411%	24,357

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.Leu10Phe
Coding: c.28C>T
MANE Select: NM_002778
dbSNP: rs779742363
Type: single nucleotide variant
Location: chr10:71851194 (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: combined PSAP deficiency

For Metachromatic leukodystrophy (Orphanet):

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

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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-leu10phe (accessed [today's date]).

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