Is SMPD1 p.Phe140= (c.420T>C) pathogenic?

SMPD1 p.Phe140= (c.420T>C) is classified Likely benign in SMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-09). Absent from gnomAD v4.1; Associated with Niemann-Pick disease type A.

What condition is associated with SMPD1 p.Phe140= (c.420T>C)?

SMPD1 p.Phe140= (c.420T>C) is associated with Niemann-Pick disease type A, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Phe140= (c.420T>C) in the general population?

SMPD1 p.Phe140= (c.420T>C) is absent from gnomAD v4.1 (gnomAD).

SMPD1 p.Phe140=

Q: How is Infantile neurovisceral acid sphingomyelinase deficiency inherited?

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

c.420T>C · rs747284877 · VCV2943043

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61	GERP -2.4, phastCons 0.044
Overall
CADD	9.734	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMPD1
Protein: p.Phe140=
Coding: c.420T>C
MANE Select: NM_000543
dbSNP: rs747284877
Type: single nucleotide variant
Location: chr11:6391485 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB
Residue 140: 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 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 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
SMPD1 c.1340+2T>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-phe140 (accessed [today's date]).

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