SLC33A1

Chr 3ARAD

solute carrier family 33 member 1

Also known as: ACATN, AT-1, AT1, CCHLND, HPBDS, SPG42

NCBI Gene: 9197ENSG00000169359UniProt: O00400

The protein encoded by this gene is required for the formation of O-acetylated (Ac) gangliosides. The encoded protein is predicted to contain 6 to 10 transmembrane domains, and a leucine zipper motif in transmembrane domain III. Defects in this gene have been reported to cause spastic paraplegia autosomal dominant type 42 (SPG42) in one Chinese family, but not in similar patients of European descent. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

Huppke-Brendel syndromeMIM #614482
AR
Spastic paraplegia 42, autosomal dominantMIM #612539
AD
314
ClinVar variants
27
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SLC33A1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
27 Pathogenic / Likely Pathogenic· 163 VUS of 314 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.81LOEUF
pLI 0.000
Z-score 2.23
OE 0.48 (0.29–0.81)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.98Z-score
OE missense 0.67 (0.60–0.76)
193 obs / 287.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.48 (0.29–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.60–0.76)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 10 / 21.0Missense obs/exp: 193 / 287.3Syn Z: -0.35

ClinVar Variant Classifications

314 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic2
VUS163
Likely Benign86
Benign16
Conflicting7
25
Pathogenic
2
Likely Pathogenic
163
VUS
86
Likely Benign
16
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
4
16
0
25
Likely Pathogenic
1
0
1
0
2
VUS
4
142
10
7
163
Likely Benign
0
11
19
56
86
Benign
0
1
14
1
16
Conflicting
—7
Total101586064299

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SLC33A1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC33A1-related congenital cataracts and hearing loss with low serum copper and ceruloplasmin

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Huppke-Brendel syndrome

MIM #614482

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 42, autosomal dominant

MIM #612539

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification and functional analysis of a SLC33A1: c.339T>G (p.Ser113Arg) variant in the original SPG42 family.
Mao F et al.·Hum Mutat
2015Functional
Overexpression of ATase1 and ATase2 disrupts the secretome and causes a progeria phenotype.
Cheng TL et al.·Life Sci Alliance
2025
Annonaceous Acetogenins Synergistically Inhibit Hepatocellular Carcinoma with Sorafenib.
Li RS et al.·J Nat Prod
2024
Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation.
Hullinger R et al.·J Exp Med
2016
A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42).
Lin P et al.·Am J Hum Genet
2008
Abnormal concentrations of acetylated amino acids in cerebrospinal fluid in acetyl-CoA transporter deficiency.
Šikić K et al.·J Inherit Metab Dis
2022
Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1.
Chiplunkar S et al.·Metab Brain Dis
2016Case report
Mutation and clinical characteristics of autosomal-dominant hereditary spastic paraplegias in China.
Luo Y et al.·Neurodegener Dis
2014
Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin.
Huppke P et al.·Am J Hum Genet
2012
The endoplasmic reticulum acetyltransferases ATase1/NAT8B and ATase2/NAT8 are differentially regulated to adjust engagement of the secretory pathway.
Rigby MJ et al.·J Neurochem
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools