SPTBN4

Chr 19AR

spectrin beta, non-erythrocytic 4

Also known as: CMND, NEDHND, QV, SPNB4, SPTBN3

NCBI Gene: 57731 ENSG00000160460 UniProt: Q9H254 OMIM: 606214

Spectrin beta 4 is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton and localizes to the nuclear matrix, PML nuclear bodies, and cytoplasmic vesicles. Mutations cause a neurodevelopmental disorder with hypotonia, neuropathy, and deafness inherited in an autosomal recessive pattern. This gene is extremely intolerant to loss-of-function variants (pLI >0.99, LOEUF 0.19), indicating that complete loss of protein function is likely deleterious.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM

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 localizes to the nuclear matrix, PML nuclear bodies, and cytoplasmic vesicles. A highly similar gene in the mouse is required for localization of specific membrane proteins in polarized regions of neurons. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.191 OMIM phenotype

Clinical Summary— SPTBN4

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with hypotonia, neuropathy, and deafness · ARDefinitive

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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ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 426 VUS of 648 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SPTBN4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 8.48

OE 0.12 (0.08–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.93Z-score

OE missense 0.70 (0.66–0.74)

958 obs / 1367.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.12 (0.08–0.19)

0≤0.351.4

Missense OE?0.70 (0.66–0.74)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 13 / 108.1Missense obs/exp: 958 / 1367.4Syn Z: 2.79

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPTBN4-related neurodevelopmental disorder with hypotonia, neuropathy, and deafnessLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.5279th %ile

GOF

0.75top 25%

LOF

0.51top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

648 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic18

VUS426

Likely Benign104

Benign55

Conflicting9

Pathogenic

Likely Pathogenic

426

VUS

104

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	1	0	0	16
Likely Pathogenic	17	1	0	0	18
VUS	3	420	3	0	426
Likely Benign	0	16	10	78	104
Benign	0	7	39	9	55
Conflicting	—				9
Total	35	445	52	87	628

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap SPTBN4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →