Is PSAP p.Ala30Ser (c.88G>T) pathogenic?

PSAP p.Ala30Ser (c.88G>T) is classified Conflicting classifications of pathogenicity in PSAP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0921); Ultra-rare (popmax 0.0667%, amr); Associated with Krabbe disease due to saposin A deficiency.

What condition is associated with PSAP p.Ala30Ser (c.88G>T)?

PSAP p.Ala30Ser (c.88G>T) is associated with Krabbe disease due to saposin A deficiency, metachromatic leukodystrophy due to saposin B deficiency, Gaucher disease due to saposin C deficiency (ClinVar).

How common is PSAP p.Ala30Ser (c.88G>T) in the general population?

PSAP p.Ala30Ser (c.88G>T) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

What do computational predictors say about PSAP p.Ala30Ser (c.88G>T)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

PSAP p.Ala30Ser

c.88G>T · rs144942998 · VCV300536

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Krabbe disease due to saposin A deficiency

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -4.99	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 7.6	GERP 1.8, phastCons 0.98
Overall
CADD	21.3	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 0.0667% Admixed American · 40/60,012 alleles

Filtering AF 0.0502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0549% 886/1,613,994 alleles · ultra-rare exomes 811/1,461,672 · genomes 75/152,322 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.14%	88
Remaining individualsnot grpmax-eligible	0.101%	992
Admixed Americangrpmax	0.0667%	1,500
Middle Eastern	0.066%	1,514
European (non-Finnish)	0.0366%	2,731
African / African-American	0.012%	8,339

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala30Ser
Coding: c.88G>T
MANE Select: NM_002778
dbSNP: rs144942998
Type: single nucleotide variant
Location: chr10:71834458 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 30: the saposin a-type 1 domain

Full PSAP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Krabbe disease due to saposin A deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: metachromatic leukodystrophy due to saposin B deficiency Gaucher disease due to saposin C deficiency combined PSAP deficiency

Similar variants

PSAP p.Ala30Val Uncertain significance ★★ ⚠ same residue
PSAP p.Ala30= 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-ala30ser (accessed [today's date]).

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