Is PSAP p.Leu6Phe (c.16C>T) pathogenic?

PSAP p.Leu6Phe (c.16C>T) is classified Benign/Likely benign in PSAP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0669); Rare (popmax 0.946%, afr); Associated with metachromatic leukodystrophy due to saposin B deficiency.

How common is PSAP p.Leu6Phe (c.16C>T) in the general population?

PSAP p.Leu6Phe (c.16C>T) is rare (popmax 0.946%, afr) (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.Leu6Phe (c.16C>T)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

PSAP p.Leu6Phe

Q: What condition is associated with PSAP p.Leu6Phe (c.16C>T)?

PSAP p.Leu6Phe (c.16C>T) is associated with metachromatic leukodystrophy due to saposin B deficiency, metachromatic leukodystrophy (ClinVar).

c.16C>T · rs148279196 · VCV791718

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.946%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -8.04	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 -1.6	GERP -3
Overall
CADD	13.56	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.946% African / African-American · 692/73,188 alleles

Filtering AF 0.887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.864%

Overall 0.0518% 804/1,551,144 alleles · rare exomes 414/1,398,758 · genomes 390/152,386 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.946%	106
Remaining individualsnot grpmax-eligible	0.0732%	1,366
Admixed American	0.0588%	1,700
Middle Eastern	0.0334%	2,990
South Asian	0.0297%	3,363
European (non-Finnish)	0.000959%	104,260

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.Leu6Phe
Coding: c.16C>T
MANE Select: NM_002778
dbSNP: rs148279196
Type: single nucleotide variant
Location: chr10:71851206 (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

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PSAP c.721-1G>A Likely pathogenic ★★ same condition
PSAP p.Asn215His Pathogenic/Likely pathogenic ★★ same condition
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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-leu6phe (accessed [today's date]).

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