Is PSAP p.Arg421Cys (c.1261C>T) pathogenic?

PSAP p.Arg421Cys (c.1261C>T) is classified Conflicting classifications of pathogenicity in PSAP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-30). AlphaMissense: likely benign (0.1944); Very rare (popmax 0.00659%, sas); Associated with Krabbe disease due to saposin A deficiency.

What condition is associated with PSAP p.Arg421Cys (c.1261C>T)?

PSAP p.Arg421Cys (c.1261C>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.Arg421Cys (c.1261C>T) in the general population?

PSAP p.Arg421Cys (c.1261C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about PSAP p.Arg421Cys (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.1944) — an in-silico prediction, not a clinical call.

PSAP p.Arg421Cys

c.1261C>T · rs529719024 · VCV300512

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Krabbe disease due to saposin A deficiency

Computational evidence

Protein change
AlphaMissense	0.1944	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -10.34	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -3.5, phastCons 0.17
Overall
CADD	21.9	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 0.00659% South Asian · 6/91,080 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000929% 15/1,614,184 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,180
East Asian	0.00446%	22,435
Remaining individualsnot grpmax-eligible	0.0016%	62,512
African / African-American	0.00133%	75,046
European (non-Finnish)	0.000424%	236,008

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.Arg421Cys
Coding: c.1261C>T
MANE Select: NM_002778
dbSNP: rs529719024
Type: single nucleotide variant
Location: chr10:71819554 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 21 PDB
Residue 421: the saposin b-type 4 domain; a disulfide bond; an α-helix

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.Arg421His Conflicting classifications of pathogenicity ★ ⚠ same residue
PSAP p.Arg421Leu 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

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-arg421cys (accessed [today's date]).

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