Is SMPD1 p.Pro332= (c.996C>G) pathogenic?

SMPD1 p.Pro332= (c.996C>G) is classified Likely benign in SMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-21). Very rare (popmax 0.000424%, nfe); Associated with Niemann-Pick disease type B.

What condition is associated with SMPD1 p.Pro332= (c.996C>G)?

SMPD1 p.Pro332= (c.996C>G) is associated with Niemann-Pick disease type B, Niemann-Pick disease type A (ClinVar).

How common is SMPD1 p.Pro332= (c.996C>G) in the general population?

SMPD1 p.Pro332= (c.996C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

SMPD1 p.Pro332=

Q: How is Chronic visceral acid sphingomyelinase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.996C>G · rs1425916722 · VCV1157977

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Niemann-Pick disease type B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.71	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP -0.86, phastCons 1
Overall
CADD	7.587	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,036 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,176 alleles · very rare exomes 5/1,461,884 · genomes 0/152,292 · 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: SMPD1
Protein: p.Pro332=
Coding: c.996C>G
MANE Select: NM_000543
dbSNP: rs1425916722
Type: single nucleotide variant
Location: chr11:6392061 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB
Residue 332: a UniProt-annotated variant site (in npdb)

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

Disease context

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

Also linked: Niemann-Pick disease type A

For Chronic visceral acid sphingomyelinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

SMPD1 p.Pro332Ser Likely pathogenic ★ ⚠ same residue
SMPD1 p.Pro332Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SMPD1 p.Pro332Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
SMPD1 p.Pro332His Conflicting classifications of pathogenicity ★ ⚠ same residue
SMPD1 p.Pro332Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SMPD1 p.Pro332Thr Uncertain significance ⚠ same residue
SMPD1 p.Pro332fs Likely pathogenic same residue
SMPD1 c.1091+1G>A 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/smpd1-p-pro332 (accessed [today's date]).

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