Is SMPD1 p.Pro66= (c.198C>T) pathogenic?

SMPD1 p.Pro66= (c.198C>T) is classified Likely benign in SMPD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-06). Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with SMPD1 p.Pro66= (c.198C>T)?

SMPD1 p.Pro66= (c.198C>T) is associated with Inborn genetic diseases, Niemann-Pick disease type A, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Pro66= (c.198C>T) in the general population?

SMPD1 p.Pro66= (c.198C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

SMPD1 p.Pro66=

c.198C>T · rs770037147 · VCV1082695

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.024	GERP -3.2
Overall
CADD	7.585	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,002 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000867% 14/1,614,010 alleles · very rare exomes 13/1,461,874 · genomes 1/152,136 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00468%	21,348
Admixed Americangrpmax	0.00333%	30,001
European (non-Finnish)	0.000763%	131,112

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro66=
Coding: c.198C>T
MANE Select: NM_000543
dbSNP: rs770037147
Type: single nucleotide variant
Location: chr11:6390796 (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 p.Pro66Leu Uncertain significance ⚠ 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
SMPD1 c.1264-2A>G 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-pro66 (accessed [today's date]).

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