SPTBN1

Chr 2AD

spectrin beta, non-erythrocytic 1

Also known as: DDISBA, ELF, HEL102, SPTB2, betaSpII

NCBI Gene: 6711 ENSG00000115306 UniProt: Q01082 OMIM: 182790

Spectrin beta chain, non-erythrocytic 1 is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton and plays a critical role in central nervous system development and function. Mutations cause autosomal dominant developmental delay with impaired speech and behavioral abnormalities. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that even single pathogenic variants can cause disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats which are involved in dimer formation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental delay, impaired speech, and behavioral abnormalitiesMIM #619475

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · developmental delay, impaired speech, and behavioral abnormalities · AD · ClinGen 2026

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 9.70

OE 0.04 (0.02–0.09)

Highly constrained

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

Missense Constraint?

4.54Z-score

OE missense 0.66 (0.62–0.70)

931 obs / 1411.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.09)

0≤0.351.4

Missense OE?0.66 (0.62–0.70)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 5 / 119.4Missense obs/exp: 931 / 1411.2Syn Z: -3.44

Background carrier burden — how many people carry a rare variant somewhere in SPTBN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

2,575 rare PASS variants

Rare truncating (LoF)

1 in 5,900

78 rare PASS variants

Rare synonymous (reference)

1 in 33

1,448 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPTBN1. 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 39	1 in 11,000
South Asian	~43k	1 in 26	1 in 6,100
Remaining (unassigned)	~30k	1 in 37	1 in 3,000
European (Finnish)	~27k	1 in 80	≈ 1 in 6,600
Admixed American	~22k	1 in 39	1 in 2,000
African / African American	~21k	1 in 36	1 in 2,200
East Asian	~20k	1 in 34	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 100	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 30	≈ 1 in 2,900

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 35 coding exons well covered in gnomAD exomes and genomes.? see exons ↓