Is SMPD1 p.Val409= (c.1227G>A) pathogenic?

SMPD1 p.Val409= (c.1227G>A) is classified Likely benign in SMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). Ultra-rare (popmax 0.0494%, mid); Associated with Niemann-Pick disease type A.

What condition is associated with SMPD1 p.Val409= (c.1227G>A)?

SMPD1 p.Val409= (c.1227G>A) is associated with Niemann-Pick disease type A, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Val409= (c.1227G>A) in the general population?

SMPD1 p.Val409= (c.1227G>A) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

SMPD1 p.Val409=

Q: How is Infantile neurovisceral acid sphingomyelinase deficiency inherited?

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

c.1227G>A · rs768283171 · VCV1110926

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

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	Δ0.77	donor gain · deltas
Pangolin	Δ0.51	gain · loss 0.25 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.69	GERP -1.7, phastCons 0.001
Overall
CADD	18.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% Middle Eastern · 3/6,076 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00105% 17/1,613,790 alleles · ultra-rare exomes 15/1,461,582 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,025
African / African-American	0.00667%	14,988
East Asian	0.00223%	44,892
South Asian	0.0011%	91,084
European (non-Finnish)	0.000593%	168,545

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.Val409=
Coding: c.1227G>A
MANE Select: NM_000543
dbSNP: rs768283171
Type: single nucleotide variant
Location: chr11:6393351 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB
Residue 409: 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.Val409fs Pathogenic ★ same residue
SMPD1 p.Val409Ala 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-val409 (accessed [today's date]).

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