Is PSAP p.His399= (c.1197C>T) pathogenic?

PSAP p.His399= (c.1197C>T) is classified Conflicting classifications of pathogenicity in PSAP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-18). Ultra-rare (popmax 0.0165%, mid); Associated with Krabbe disease due to saposin A deficiency.

What condition is associated with PSAP p.His399= (c.1197C>T)?

PSAP p.His399= (c.1197C>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.His399= (c.1197C>T) in the general population?

PSAP p.His399= (c.1197C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

PSAP p.His399=

c.1197C>T · rs748761213 · VCV879388

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Krabbe disease due to saposin A 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
Pangolin	Δ0.23	gain · loss 0.07 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -7.9	GERP -3.5
Overall
CADD	3.292	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00149% 24/1,614,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00333%	30,014
African / African-American	0.00266%	37,525
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.00153%	65,557

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.His399=
Coding: c.1197C>T
MANE Select: NM_002778
dbSNP: rs748761213
Type: single nucleotide variant
Location: chr10:71819618 (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

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.His399Tyr Uncertain significance ★ ⚠ same residue
PSAP p.His399Arg 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-his399 (accessed [today's date]).

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