Is PSAP p.Pro170Ala (c.508C>G) pathogenic?

PSAP p.Pro170Ala (c.508C>G) is classified Uncertain significance in PSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: ambiguous (0.4046); Absent from gnomAD v4.1; Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Pro170Ala (c.508C>G)?

PSAP p.Pro170Ala (c.508C>G) is associated with metachromatic leukodystrophy due to saposin B deficiency, Gaucher disease due to saposin C deficiency, combined PSAP deficiency (ClinVar).

How common is PSAP p.Pro170Ala (c.508C>G) in the general population?

PSAP p.Pro170Ala (c.508C>G) 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.Pro170Ala (c.508C>G)?

AlphaMissense predicts ambiguous (score 0.4046) — an in-silico prediction, not a clinical call.

PSAP p.Pro170Ala

c.508C>G · rs761637109 · VCV879499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4046 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
AlphaMissense	0.4046	ambiguous
REVEL	0.614	indeterminate
SaProt	LLR -6.39	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Overall
CADD	26.7	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

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.Pro170Ala
Coding: c.508C>G
MANE Select: NM_002778
dbSNP: rs761637109
Type: single nucleotide variant
Location: chr10:71828945 (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: Gaucher disease due to saposin C deficiency combined PSAP deficiency Krabbe disease due to saposin A deficiency

For Metachromatic leukodystrophy (Orphanet):

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

Similar variants

PSAP p.Pro170= 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
PSAP p.Asn215Lys 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-pro170ala (accessed [today's date]).

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