SPTLC1

Chr 9AD

serine palmitoyltransferase long chain base subunit 1

Also known as: ALS27, HSAN1, HSN1, LBC1, LCB1, SPT1, SPTI

NCBI Gene: 10558ENSG00000090054UniProt: O15269

This gene encodes a member of the class-II pyridoxal-phosphate-dependent aminotransferase family. The encoded protein is the long chain base subunit 1 of serine palmitoyltransferase. Serine palmitoyltransferase converts L-serine and palmitoyl-CoA to 3-oxosphinganine with pyridoxal 5'-phosphate and is the key enzyme in sphingolipid biosynthesis. Mutations in this gene were identified in patients with hereditary sensory neuropathy type 1. Alternatively spliced variants encoding different isoforms have been identified. Pseudogenes of this gene have been defined on chromosomes 1, 6, 10, and 13. [provided by RefSeq, Jul 2013]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 27, juvenileMIM #620285
AD
Neuropathy, hereditary sensory and autonomic, type IAMIM #162400
AD
573
ClinVar variants
43
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SPTLC1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 310 VUS of 573 total submissions

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.
0.98LOEUF
pLI 0.000
Z-score 1.65
OE 0.68 (0.48–0.98)
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.
1.13Z-score
OE missense 0.80 (0.72–0.90)
208 obs / 259.2 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.0.68 (0.48–0.98)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.72–0.90)
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: 21 / 30.9Missense obs/exp: 208 / 259.2Syn Z: -0.30

ClinVar Variant Classifications

573 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic11
VUS310
Likely Benign187
Benign14
Conflicting19
32
Pathogenic
11
Likely Pathogenic
310
VUS
187
Likely Benign
14
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
7
25
0
32
Likely Pathogenic
0
5
6
0
11
VUS
29
216
63
2
310
Likely Benign
0
12
94
81
187
Benign
0
1
12
1
14
Conflicting
—19
Total2924120084573

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

View in ClinVar →

Protein Context — Lollipop Plot

SPTLC1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Amyotrophic lateral sclerosis 27, juvenile

MIM #620285

Molecular basis of disorder known

Autosomal dominant

Neuropathy, hereditary sensory and autonomic, type IA

MIM #162400

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SPTLC1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
Johnson JO et al.·JAMA Neurol
2021
Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations.
Wang P et al.·Chin Med J (Engl)
2023Review
Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
Okubo S et al.·J Neurol
2024Functional
Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.
Gantner ML et al.·N Engl J Med
2019
Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
Mohassel P et al.·Nat Med
2021
Hereditary sensory neuropathies.
Auer-Grumbach M·Drugs Today (Barc)
2004Review
Mutation screening of SPTLC1 and SPTLC2 in amyotrophic lateral sclerosis.
Li C et al.·Hum Genomics
2023
Cardiomyocyte Krüppel-Like Factor 5 Promotes De Novo Ceramide Biosynthesis and Contributes to Eccentric Remodeling in Ischemic Cardiomyopathy.
Hoffman M et al.·Circulation
2021Functional
Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.
Syeda SB et al.·J Neurol Neurosurg Psychiatry
2024
The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment.
Fiorillo C et al.·Neuropathol Appl Neurobiol
2022
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