Is PSAP p.Pro394Ser (c.1180C>T) pathogenic?

PSAP p.Pro394Ser (c.1180C>T) is classified Uncertain significance in PSAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1027); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with PSAP p.Pro394Ser (c.1180C>T)?

PSAP p.Pro394Ser (c.1180C>T) is associated with Inborn genetic diseases, metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Pro394Ser (c.1180C>T) in the general population?

PSAP p.Pro394Ser (c.1180C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PSAP p.Pro394Ser (c.1180C>T)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

PSAP p.Pro394Ser

c.1180C>T · rs535856610 · VCV1449204

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -7.19	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 6	GERP -0.44, phastCons 1
Overall
CADD	16.21	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 0.00133% African / African-American · 1/75,044 alleles

Overall 0.000124% 2/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,044
South Asian	0.0011%	91,084

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.Pro394Ser
Coding: c.1180C>T
MANE Select: NM_002778
dbSNP: rs535856610
Type: single nucleotide variant
Location: chr10:71819726 (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

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

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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-pro394ser (accessed [today's date]).

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