Is SMPD1 p.Val147= (c.441G>A) pathogenic?

SMPD1 p.Val147= (c.441G>A) is classified Conflicting classifications of pathogenicity in SMPD1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.698%, afr); Associated with Niemann-Pick disease type A.

What condition is associated with SMPD1 p.Val147= (c.441G>A)?

SMPD1 p.Val147= (c.441G>A) is associated with Niemann-Pick disease type A, Niemann-Pick disease, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Val147= (c.441G>A) in the general population?

SMPD1 p.Val147= (c.441G>A) is rare (popmax 0.698%, afr) (gnomAD).

SMPD1 p.Val147=

Q: How is Infantile neurovisceral acid sphingomyelinase deficiency inherited?

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

c.441G>A · rs148944108 · VCV287033

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.698%, afr)

Conditions

Niemann-Pick disease type A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.67	donor gain · deltas
Pangolin	Δ0.55	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.9	GERP -0.88, phastCons 1
Overall
CADD	18.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.698% African / African-American · 524/75,072 alleles

Filtering AF 0.649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.629%

Overall 0.0489% 790/1,614,080 alleles · rare exomes 445/1,461,690 · genomes 345/152,390 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.698%	143
Admixed American	0.185%	541
Remaining individualsnot grpmax-eligible	0.064%	1,562
Middle Eastern	0.0505%	1,982
European (non-Finnish)	0.00949%	10,536

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.Val147=
Coding: c.441G>A
MANE Select: NM_000543
dbSNP: rs148944108
Type: single nucleotide variant
Location: chr11:6391506 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB
Residue 147: an α-helix; the saposin b-type domain

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 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.Val147Met Uncertain significance ★ same residue
SMPD1 p.Val147Ala 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

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-val147 (accessed [today's date]).

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