Is SMPD1 p.Pro191= (c.573T>C) pathogenic?

SMPD1 p.Pro191= (c.573T>C) is classified Likely benign in SMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). Rare (popmax 0.762%, afr); Associated with Niemann-Pick disease type A.

What condition is associated with SMPD1 p.Pro191= (c.573T>C)?

SMPD1 p.Pro191= (c.573T>C) is associated with Niemann-Pick disease type A, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Pro191= (c.573T>C) in the general population?

SMPD1 p.Pro191= (c.573T>C) is rare (popmax 0.762%, afr) (gnomAD).

SMPD1 p.Pro191=

Q: How is Infantile neurovisceral acid sphingomyelinase deficiency inherited?

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

c.573T>C · rs751653824 · VCV1090689

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.762%, afr)

Conditions

Niemann-Pick disease type A

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 -3	GERP -2.5
Overall
CADD	4.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.762% African / African-American · 133/17,454 alleles

Filtering AF 0.657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.617%

Overall 0.284% 956/336,080 alleles · rare exomes 430/314,960 · genomes 526/21,120 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.04%	96
Finnishnot grpmax-eligible	0.927%	108
African / African-Americangrpmax	0.762%	131
East Asian	0.468%	214
Ashkenazi Jewishnot grpmax-eligible	0.437%	229
Admixed American	0.271%	370
European (non-Finnish)	0.227%	440
South Asian	0.19%	527
Middle Eastern	0.171%	585
Remaining individualsnot grpmax-eligible	0.143%	698

Amish 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.Pro191=
Coding: c.573T>C
MANE Select: NM_000543
dbSNP: rs751653824
Type: single nucleotide variant
Location: chr11:6391638 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB
Residue 191: an α-helix

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

Disease context

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

Also linked: Niemann-Pick disease type B

For Infantile neurovisceral acid sphingomyelinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

SMPD1 p.Pro191fs Pathogenic/Likely pathogenic ★★ same residue
SMPD1 p.Pro191_Ser192insTer Pathogenic ★ 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-pro191 (accessed [today's date]).

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