Is PSAP p.Met1Val (c.1A>G) pathogenic?

PSAP p.Met1Val (c.1A>G) is classified Pathogenic in PSAP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-19). Very rare (popmax 0.00274%, afr); Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Met1Val (c.1A>G)?

PSAP p.Met1Val (c.1A>G) is associated with metachromatic leukodystrophy due to saposin B deficiency, metachromatic leukodystrophy, Parkinson disease 24, autosomal dominant, susceptibility to (ClinVar).

How common is PSAP p.Met1Val (c.1A>G) in the general population?

PSAP p.Met1Val (c.1A>G) is very rare (popmax 0.00274%, afr) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

PSAP p.Met1Val

c.1A>G · rs121918106 · VCV860182

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

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.
Consequence	start-loss	predicted loss-of-function in a LoF-intolerant gene
REVEL	0.472	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00274% African / African-American · 2/73,062 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.00058% 9/1,550,968 alleles · very rare exomes 7/1,398,710 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00274%	36,531
East Asian	0.00244%	40,934
European (non-Finnish)	0.000523%	191,142

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.Met1Val
Coding: c.1A>G
MANE Select: NM_002778
dbSNP: rs121918106
Type: single nucleotide variant
Location: chr10:71851221 (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: metachromatic leukodystrophy Parkinson disease 24, autosomal dominant, susceptibility to

For Metachromatic leukodystrophy (Orphanet):

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

Similar variants

PSAP p.Met1Arg Pathogenic/Likely pathogenic ★★ same residue
PSAP p.Met1Leu Pathogenic ★★ 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-met1val (accessed [today's date]).

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