Is PSAP p.Val70Phe (c.208G>T) pathogenic?

PSAP p.Val70Phe (c.208G>T) is classified Likely benign in PSAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.2331); Rare (popmax 0.2%, amr); Associated with metachromatic leukodystrophy due to saposin B deficiency.

What condition is associated with PSAP p.Val70Phe (c.208G>T)?

PSAP p.Val70Phe (c.208G>T) is associated with metachromatic leukodystrophy due to saposin B deficiency (ClinVar).

How common is PSAP p.Val70Phe (c.208G>T) in the general population?

PSAP p.Val70Phe (c.208G>T) is rare (popmax 0.2%, amr) (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.Val70Phe (c.208G>T)?

AlphaMissense predicts likely benign (score 0.2331) — an in-silico prediction, not a clinical call.

PSAP p.Val70Phe

c.208G>T · rs750239809 · VCV798198

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2331 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.2%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

metachromatic leukodystrophy due to saposin B deficiency

Computational evidence

Protein change
AlphaMissense	0.2331	likely benign
REVEL	0.548	indeterminate
SaProt	LLR -10.91	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -2.6, phastCons 0.24
Overall
CADD	18.79	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

Grpmax group 0.2% Admixed American · 120/60,006 alleles

Filtering AF 0.171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.16%

Overall 0.00744% 120/1,613,976 alleles · rare exomes 91/1,461,796 · genomes 29/152,180 · joint denominator

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.Val70Phe
Coding: c.208G>T
MANE Select: NM_002778
dbSNP: rs750239809
Type: single nucleotide variant
Location: chr10:71831887 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 70: the saposin b-type 1 domain; a UniProt-annotated variant site (in krbsapa; unable to mobilize lipids out of the membrane); 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.Val70= Likely benign ★ same residue
PSAP p.Val70del Uncertain significance ★ same residue
PSAP p.Val70Gly 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

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-val70phe (accessed [today's date]).

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