Is PSAP p.Ser133Pro (c.397T>C) pathogenic?

PSAP p.Ser133Pro (c.397T>C) is classified Uncertain significance in PSAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-27). AlphaMissense: likely pathogenic (0.5978); Very rare (popmax 0.00446%, eas); Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Ser133Pro (c.397T>C)?

PSAP p.Ser133Pro (c.397T>C) is associated with metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Ser133Pro (c.397T>C) in the general population?

PSAP p.Ser133Pro (c.397T>C) is very rare (popmax 0.00446%, eas) (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.Ser133Pro (c.397T>C)?

AlphaMissense predicts likely pathogenic (score 0.5978) — an in-silico prediction, not a clinical call.

PSAP p.Ser133Pro

c.397T>C · rs2133045059 · VCV1414967

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
AlphaMissense	0.5978	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -12.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.7, phastCons 1
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000274% 4/1,461,836 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
Remaining individualsnot grpmax-eligible	0.0016%	62,502
South Asian	0.0011%	91,080

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.Ser133Pro
Coding: c.397T>C
MANE Select: NM_002778
dbSNP: rs2133045059
Type: single nucleotide variant
Location: chr10:71829056 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 133: the saposin b-type 1 domain; an α-helix

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

PSAP p.Ser133Cys Uncertain significance ★★ ⚠ same residue
PSAP p.Ser133= 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-ser133pro (accessed [today's date]).

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