Is SMPD1 p.Pro58= (c.174G>C) pathogenic?

SMPD1 p.Pro58= (c.174G>C) is classified Likely benign in SMPD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-28). Very rare (popmax 8.48e-05%, nfe); Associated with Niemann-Pick disease type B.

What condition is associated with SMPD1 p.Pro58= (c.174G>C)?

SMPD1 p.Pro58= (c.174G>C) is associated with Niemann-Pick disease type B, Niemann-Pick disease type A (ClinVar).

How common is SMPD1 p.Pro58= (c.174G>C) in the general population?

SMPD1 p.Pro58= (c.174G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

SMPD1 p.Pro58=

Q: How is Chronic visceral acid sphingomyelinase deficiency inherited?

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

c.174G>C · rs368143181 · VCV1779373

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Niemann-Pick disease type B

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
Constraint at this position
Conservation	phyloP -5.1	GERP -4
Overall
CADD	0.441	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,898 alleles

Overall 6.2e-05% 1/1,613,866 alleles · very rare exomes 1/1,461,744 · genomes 0/152,122 · 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.Pro58=
Coding: c.174G>C
MANE Select: NM_000543
dbSNP: rs368143181
Type: single nucleotide variant
Location: chr11:6390772 (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 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 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
SMPD1 c.1264-2A>G Likely pathogenic ★★ same condition
SMPD1 c.1340+2T>C 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-pro58 (accessed [today's date]).

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