Is SMPD1 p.Pro477= (c.1431G>A) pathogenic?

SMPD1 p.Pro477= (c.1431G>A) is classified Likely benign in SMPD1 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-04). Very rare (popmax 0.00667%, afr); Associated with Niemann-Pick disease type B.

What condition is associated with SMPD1 p.Pro477= (c.1431G>A)?

SMPD1 p.Pro477= (c.1431G>A) is associated with Niemann-Pick disease type B, Niemann-Pick disease type A (ClinVar).

How common is SMPD1 p.Pro477= (c.1431G>A) in the general population?

SMPD1 p.Pro477= (c.1431G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

SMPD1 p.Pro477=

Q: How is Chronic visceral acid sphingomyelinase deficiency inherited?

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

c.1431G>A · rs138588535 · VCV763759

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Conditions

Niemann-Pick disease type B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.003	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3
Overall
CADD	0.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,914 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00427% 69/1,614,072 alleles · very rare exomes 65/1,461,886 · genomes 4/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,983
South Asian	0.00549%	18,218
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00458%	21,853
East Asian	0.00446%	22,446

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.Pro477=
Coding: c.1431G>A
MANE Select: NM_000543
dbSNP: rs138588535
Type: single nucleotide variant
Location: chr11:6393986 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB
Residue 477: a UniProt-annotated variant site (in npda and npdb); a β-strand

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.Pro477Leu Pathogenic/Likely pathogenic ★★ same residue
SMPD1 p.Pro477Thr Likely pathogenic ★★ same residue
SMPD1 p.Pro477Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro477 (accessed [today's date]).

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