Is SMPD1 p.Pro533= (c.1599G>A) pathogenic?

SMPD1 p.Pro533= (c.1599G>A) is classified Conflicting classifications of pathogenicity in SMPD1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-27). Rare (popmax 0.5%, sas); Associated with Niemann-Pick disease.

What condition is associated with SMPD1 p.Pro533= (c.1599G>A)?

SMPD1 p.Pro533= (c.1599G>A) is associated with Niemann-Pick disease, Niemann-Pick disease type A, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Pro533= (c.1599G>A) in the general population?

SMPD1 p.Pro533= (c.1599G>A) is rare (popmax 0.5%, sas) (gnomAD).

SMPD1 p.Pro533=

c.1599G>A · rs552841217 · VCV286896

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.5%, sas)

Conditions

Niemann-Pick disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.01	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.4	GERP -3.3
Overall
CADD	0.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.5% South Asian · 455/91,088 alleles

Filtering AF 0.462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.447%

Overall 0.0314% 507/1,614,198 alleles · rare exomes 478/1,461,868 · genomes 29/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.5%	200
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0384%	2,604
East Asian	0.00668%	14,960
African / African-American	0.00266%	37,533
European (non-Finnish)	0.00169%	59,001

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: SMPD1
Protein: p.Pro533=
Coding: c.1599G>A
MANE Select: NM_000543
dbSNP: rs552841217
Type: single nucleotide variant
Location: chr11:6394310 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB

Full SMPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Niemann-Pick disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease type A Niemann-Pick disease type B

Similar variants

SMPD1 p.Pro533Gln Pathogenic/Likely pathogenic ★★ same residue
SMPD1 p.Pro533Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SMPD1 c.1091+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMPD1 c.1092-1G>C Pathogenic ★★ same condition
SMPD1 c.1263+1G>A Likely pathogenic ★★ same condition
SMPD1 c.1264-1G>A Pathogenic/Likely pathogenic ★★ same condition
SMPD1 c.1264-1G>C Pathogenic/Likely pathogenic ★★ same condition
SMPD1 c.1264-1G>T 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/smpd1-p-pro533 (accessed [today's date]).

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