SPTAN1

Chr 9

spectrin alpha, non-erythrocytic 1

Also known as: DEE5, DEVEP, EIEE5, HMN11, HMND11, NEAS, SPG91, SPTA2

NCBI Gene: 6709 ENSG00000197694 UniProt: Q13813

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2010]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 5

UniProtDevelopmental delay with or without epilepsy

UniProtNeuronopathy, distal hereditary motor, autosomal dominant 11

UniProtSpastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · genetic developmental and epileptic encephalopathy · AD · ClinGen 2019
Definitive · developmental and epileptic encephalopathy, 5 · AD · Laboratory for Molecular Medicine
Strong · spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia · AD · PanelApp Australia
Strong · neuronopathy, distal hereditary motor, autosomal dominant 11 · AD · PanelApp Australia
Limited · hereditary spastic paraplegia · AR · PanelApp Australia — not for standalone diagnostic reporting

Interpreting a novel variant

A dominant-negative effect is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.10

LOEUF· LoF intol.

DN*

Mechanism· G2P

📖

GeneReview available — SPTAN1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in SPTAN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 36

2,281 rare PASS variants

Rare truncating (LoF)

1 in 690

157 rare PASS variants

Rare synonymous (reference)

1 in 28

1,265 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPTAN1. 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 45	1 in 690
South Asian	~43k	1 in 32	1 in 690
Remaining (unassigned)	~30k	1 in 31	1 in 1,000
European (Finnish)	~27k	1 in 88	1 in 1,400
Admixed American	~22k	1 in 33	1 in 390
African / African American	~21k	1 in 31	1 in 550
East Asian	~20k	1 in 31	1 in 820
Ashkenazi Jewish	~13k	1 in 100	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 34	≈ 1 in 650

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): 54 of 56 coding exons well covered in gnomAD exomes; exons 12, 37 marginal. Genomes: all 56.? see exons ↓