SPTLC2

Chr 14AD

serine palmitoyltransferase long chain base subunit 2

Also known as: HSN1C, LCB2, LCB2A, NSAN1C, SPT2, hLCB2a

NCBI Gene: 9517 ENSG00000100596 UniProt: O15270 OMIM: 605713

The SPTLC2 protein forms the catalytic core of serine palmitoyltransferase, the rate-limiting enzyme in sphingolipid biosynthesis that condenses L-serine with palmitoyl-CoA to generate long-chain bases. Mutations cause hereditary sensory and autonomic neuropathy type IC, an autosomal dominant peripheral neuropathy affecting sensory and autonomic nerve function. This gene is highly constrained against loss-of-function variants (LOEUF 0.39), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a long chain base subunit of serine palmitoyltransferase. Serine palmitoyltransferase, which consists of two different subunits, is the key enzyme in sphingolipid biosynthesis. It catalyzes the pyridoxal-5-prime-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine. Mutations in this gene were identified in patients with hereditary sensory neuropathy type I. [provided by RefSeq, Mar 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neuropathy, hereditary sensory and autonomic, type ICMIM #613640

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

—

Mechanism

📖

GeneReview available — SPTLC2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.780

Z-score 3.92

OE 0.19 (0.10–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.04Z-score

OE missense 0.68 (0.60–0.76)

210 obs / 311.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.39)

0≤0.351.4

Missense OE?0.68 (0.60–0.76)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 5 / 27.0Missense obs/exp: 210 / 311.0Syn Z: -0.63

Background carrier burden — how many people carry a rare variant somewhere in SPTLC2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

573 rare PASS variants

Rare truncating (LoF)

1 in 4,500

57 rare PASS variants

Rare synonymous (reference)

1 in 120

284 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPTLC2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 250	1 in 4,100
South Asian	~43k	1 in 91	1 in 4,900
Remaining (unassigned)	~30k	1 in 120	1 in 5,000
European (Finnish)	~27k	1 in 440	≈ 1 in 10,000
Admixed American	~22k	1 in 150	≈ 1 in 5,400
African / African American	~21k	1 in 98	≈ 1 in 6,000
East Asian	~20k	1 in 130	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 650	none seen
Middle Eastern	~2,884	1 in 160	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 12 coding exons well covered in gnomAD exomes and genomes.? see exons ↓