SYNE1

Chr 6ARAD

spectrin repeat containing nuclear envelope protein 1

Also known as: 8B, AMC3, AMCM, ARCA1, C6orf98, CPG2, EDMD4, KASH1

NCBI Gene: 23345ENSG00000131018UniProt: Q8NF91

This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Arthrogryposis multiplex congenita 3, myogenic typeMIM #618484
AR
Emery-Dreifuss muscular dystrophy 4, autosomal dominantMIM #612998
AD
Spinocerebellar ataxia, autosomal recessive 8MIM #610743
AR
7096
ClinVar variants
32
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SYNE1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 237 VUS of 7096 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.42LOEUF
pLI 0.000
Z-score 12.81
OE 0.37 (0.33–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.29Z-score
OE missense 1.01 (0.99–1.04)
4465 obs / 4410.7 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.33–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.99–1.04)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 182 / 487.0Missense obs/exp: 4465 / 4410.7Syn Z: -1.64

ClinVar Variant Classifications

7096 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic17
VUS237
Likely Benign161
Benign1
Conflicting3
15
Pathogenic
17
Likely Pathogenic
237
VUS
161
Likely Benign
1
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
6
0
15
Likely Pathogenic
10
1
6
0
17
VUS
1
221
13
2
237
Likely Benign
0
3
59
99
161
Benign
0
0
1
0
1
Conflicting
—3
Total2022585101434

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

View in ClinVar →

Protein Context — Lollipop Plot

SYNE1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SYNE1-related spinocerebellar ataxia

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Arthrogryposis multiplex congenita 3, myogenic type

MIM #618484

Molecular basis of disorder known

Autosomal recessive

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

MIM #612998

Molecular basis of disorder known

Autosomal dominant

Spinocerebellar ataxia, autosomal recessive 8

MIM #610743

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Recessive ataxias.
Synofzik M et al.·Handb Clin Neurol
2018Review
Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes.
Nadeu F et al.·Blood
2020
Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.
Coutelier M et al.·JAMA Neurol
2018
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.
Sun M et al.·Genet Med
2019Cohort
Fine-mapping genomic loci refines bipolar disorder risk genes.
Koromina M et al.·Nat Neurosci
2025
SYNE1-ataxia: Novel genotypic and phenotypic findings.
Indelicato E et al.·Parkinsonism Relat Disord
2019
Heterogeneity in clinical features and disease severity in ataxia-associated SYNE1 mutations.
Wiethoff S et al.·J Neurol
2016
Diagnosis of hereditary ataxias: a real-world single center experience.
Meli A et al.·J Neurol
2025
Multi-omics insights into the molecular signature and prognosis of hypopharyngeal squamous cell carcinoma.
Ren Y et al.·Commun Biol
2025
Expression and clinical significance of SYNE1 and MAGI2 gene promoter methylation in gastric cancer.
Qu Y et al.·Medicine (Baltimore)
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SYNE1 Deficiency Manifesting Primarily With Motor Neuron Disease.
Senghor HVF et al.·Neurol Genet
2025🔓 Open Access
Co-mutation of PCLO and SYNE1 defines an immune-activated endometrial cancer subtype with favorable prognosis.
Wu C et al.·J Obstet Gynaecol Res
2025🔓 Open Access
Two Cases of Autosomal Recessive Spinocerebellar Ataxia-8 Showing Two Novel Variants of SYNE1 in Japanese Families.
Yunoki T et al.·Intern Med
2026🔓 Open AccessCohort
Intronic SYNE1 Gene Novel Variant Associated with Myocardial Infarction in Young People with a Family History of Premature Atherosclerosis: A Case-Control Study in the Polish Population.
Ambroziak M et al.·Int J Mol Sci
2025🔓 Open Access
Challenging Diagnosis of a Patient with Two Novel Variants in the SYNE1 Gene.
Kuchina A et al.·Int J Mol Sci
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools