Is PSAP p.Val52Ile (c.154G>A) pathogenic?

PSAP p.Val52Ile (c.154G>A) is classified Uncertain significance in PSAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-03). AlphaMissense: likely benign (0.0724); Ultra-rare (popmax 0.0165%, mid); Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Val52Ile (c.154G>A)?

PSAP p.Val52Ile (c.154G>A) is associated with metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Val52Ile (c.154G>A) in the general population?

PSAP p.Val52Ile (c.154G>A) is ultra-rare (popmax 0.0165%, mid) (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.Val52Ile (c.154G>A)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

PSAP p.Val52Ile

c.154G>A · rs147920923 · VCV2151565

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -9.32	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 1.8	GERP 0.74, phastCons 0.93
Overall
CADD	22.4	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 0.0165% Middle Eastern · 1/6,066 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.0013% 21/1,613,806 alleles · ultra-rare exomes 16/1,461,570 · genomes 5/152,236 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,066
African / African-American	0.0107%	9,367
East Asian	0.00668%	14,967
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000593%	168,577

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.Val52Ile
Coding: c.154G>A
MANE Select: NM_002778
dbSNP: rs147920923
Type: single nucleotide variant
Location: chr10:71834392 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 52: the saposin a-type 1 domain

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

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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
PSAP p.Asn215Lys Pathogenic/Likely pathogenic ★★ same condition
PSAP p.Cys241Ser 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-val52ile (accessed [today's date]).

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