Is PSAP p.Ser347= (c.1041G>A) pathogenic?

PSAP p.Ser347= (c.1041G>A) is classified Likely benign in PSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-22). Very rare (popmax 0.00329%, sas); Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Ser347= (c.1041G>A)?

PSAP p.Ser347= (c.1041G>A) is associated with metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Ser347= (c.1041G>A) in the general population?

PSAP p.Ser347= (c.1041G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PSAP p.Ser347=

c.1041G>A · rs747117207 · VCV1548736

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.5
Overall
CADD	0.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000496% 8/1,614,018 alleles · very rare exomes 7/1,461,844 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,926
European (non-Finnish)	0.000169%	590,023

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.Ser347=
Coding: c.1041G>A
MANE Select: NM_002778
dbSNP: rs747117207
Type: single nucleotide variant
Location: chr10:71819865 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 347: the saposin b-type 3 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.Ser347Leu Uncertain significance ★ ⚠ 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-ser347 (accessed [today's date]).

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