Is PSAP p.Arg520His (c.1559G>A) pathogenic?

PSAP p.Arg520His (c.1559G>A) is classified Uncertain significance in PSAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-01). AlphaMissense: likely benign (0.0943); Ultra-rare (popmax 0.0333%, amr); Associated with Inborn genetic diseases.

What condition is associated with PSAP p.Arg520His (c.1559G>A)?

PSAP p.Arg520His (c.1559G>A) is associated with Inborn genetic diseases, metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Arg520His (c.1559G>A) in the general population?

PSAP p.Arg520His (c.1559G>A) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about PSAP p.Arg520His (c.1559G>A)?

AlphaMissense predicts likely benign (score 0.0943) — an in-silico prediction, not a clinical call.

PSAP p.Arg520His

c.1559G>A · rs545627914 · VCV2050467

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0943 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0943	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.6, phastCons 1
Overall
CADD	26.4	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 0.0333% Admixed American · 20/60,030 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00155% 25/1,614,188 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,001
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	8.47e-05%	1,180,013

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.Arg520His
Coding: c.1559G>A
MANE Select: NM_002778
dbSNP: rs545627914
Type: single nucleotide variant
Location: chr10:71817457 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 520: the saposin a-type 2 domain

Full PSAP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: metachromatic leukodystrophy due to saposin B deficiency

Similar variants

PSAP p.Arg520Cys Uncertain significance ★ same residue
PSAP p.Arg520= 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-arg520his (accessed [today's date]).

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