Is SMPD1 p.Pro331Ser (c.991C>T) pathogenic?

SMPD1 p.Pro331Ser (c.991C>T) is classified Uncertain significance in SMPD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-16). AlphaMissense: ambiguous (0.4969); Ultra-rare (popmax 0.0116%, nfe); Associated with Niemann-Pick disease type A.

What condition is associated with SMPD1 p.Pro331Ser (c.991C>T)?

SMPD1 p.Pro331Ser (c.991C>T) is associated with Niemann-Pick disease type A, Niemann-Pick disease type B (ClinVar).

How common is SMPD1 p.Pro331Ser (c.991C>T) in the general population?

SMPD1 p.Pro331Ser (c.991C>T) is ultra-rare (popmax 0.0116%, nfe) (gnomAD).

What do computational predictors say about SMPD1 p.Pro331Ser (c.991C>T)?

AlphaMissense predicts ambiguous (score 0.4969) — an in-silico prediction, not a clinical call.

SMPD1 p.Pro331Ser

Q: How is Infantile neurovisceral acid sphingomyelinase deficiency inherited?

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

c.991C>T · rs142476839 · VCV878122

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4969 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Niemann-Pick disease type A

Computational evidence

Protein change
AlphaMissense	0.4969	ambiguous
REVEL	0.749	pathogenic-leaning
SaProt	LLR -11.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,005 bp · p 0.7 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0116% European (non-Finnish) · 137/1,179,984 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00939%

Overall 0.00886% 143/1,613,864 alleles · ultra-rare exomes 136/1,461,702 · genomes 7/152,162 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0116%	8,613
Remaining individualsnot grpmax-eligible	0.0096%	10,412

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.Pro331Ser
Coding: c.991C>T
MANE Select: NM_000543
dbSNP: rs142476839
Type: single nucleotide variant
Location: chr11:6392056 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.37 · 4 PDB

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.Pro331= Likely benign ★ 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
SMPD1 c.1264-2A>G 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-pro331ser (accessed [today's date]).

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