Is SMPD1 p.Pro375= (c.1125C>T) pathogenic?

SMPD1 p.Pro375= (c.1125C>T) is classified Likely benign in SMPD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-01). Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with SMPD1 p.Pro375= (c.1125C>T)?

SMPD1 p.Pro375= (c.1125C>T) is associated with Inborn genetic diseases, Niemann-Pick disease type A, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Pro375= (c.1125C>T) in the general population?

SMPD1 p.Pro375= (c.1125C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

SMPD1 p.Pro375=

c.1125C>T · rs376871416 · VCV1136005

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.88 · evaluated, not missing
Constraint at this position
Conservation	phyloP -6	GERP -3.4
Overall
CADD	1.368	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,924 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00211% 34/1,613,870 alleles · ultra-rare exomes 25/1,461,672 · genomes 9/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,365
Admixed American	0.00667%	15,003
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,232
European (non-Finnish)	0.00153%	65,548
South Asian	0.0011%	91,080

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.Pro375=
Coding: c.1125C>T
MANE Select: NM_000543
dbSNP: rs376871416
Type: single nucleotide variant
Location: chr11:6393249 (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

Inborn genetic diseases — 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 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-pro375 (accessed [today's date]).

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