SPTAN1

Chr 9AD

spectrin alpha, non-erythrocytic 1

ENSG00000197694 UniProt: Q13813 OMIM: 182810

The protein functions as a cytoskeletal scaffold protein that stabilizes the plasma membrane and organizes intracellular organelles, and is also involved in DNA repair and cell cycle regulation. Mutations cause a spectrum of autosomal dominant neurological disorders including developmental and epileptic encephalopathy, developmental delay with or without epilepsy, distal hereditary motor neuronopathy, and spastic paraplegia with or without cerebellar ataxia. The gene is highly intolerant to loss-of-function variants, and mutations can cause disease predominantly through haploinsufficiency, though the broad phenotypic spectrum suggests variant-dependent mechanisms may contribute.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.104 OMIM phenotypes

Clinical Summary— SPTAN1

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 10.47

OE 0.06 (0.03–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.52Z-score

OE missense 0.58 (0.55–0.62)

802 obs / 1379.2 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.10)

0≤0.351.4

Missense OE?0.58 (0.55–0.62)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 8 / 143.2Missense obs/exp: 802 / 1379.2Syn Z: -1.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPTAN1-related neurodevelopmental disorder with epilepsy and spastic paraplegiaDNAD

This gene — mechanism propensity

0.5477th %ile

GOF

0.6737th %ile

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.10 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNaken together, these findings implicate aII spectrin in critical aspects of dendritic and axonal development and synaptogenesis, and support a dominant-negative mechanism of SPTAN1 mutations in EIEE5.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References