SYNE2

Chr 14AD

spectrin repeat containing nuclear envelope protein 2

Also known as: EDMD5, KASH2, NUA, NUANCE, Nesp2, Nesprin-2, SYNE-2, TROPH

NCBI Gene: 23224ENSG00000054654UniProt: Q8WXH0

The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

Primary Disease Associations & Inheritance

Emery-Dreifuss muscular dystrophy 5, autosomal dominantMIM #612999
AD
4838
ClinVar variants
3
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SYNE2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
3 Pathogenic / Likely Pathogenic· 358 VUS of 4838 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.
0.37LOEUF
pLI 0.000
Z-score 12.12
OE 0.32 (0.27–0.37)
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.
-1.45Z-score
OE missense 1.07 (1.04–1.10)
3624 obs / 3385.8 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.0.32 (0.27–0.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (1.04–1.10)
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.1.08
0≤1.21.6
LoF obs/exp: 118 / 369.3Missense obs/exp: 3624 / 3385.8Syn Z: -2.15

ClinVar Variant Classifications

4838 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic3
VUS358
Likely Benign152
Benign2
Conflicting5
3
Likely Pathogenic
358
VUS
152
Likely Benign
2
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
3
0
0
0
3
VUS
13
331
13
1
358
Likely Benign
0
7
67
78
152
Benign
0
0
1
1
2
Conflicting
—5
Total163388180520

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

View in ClinVar →

Protein Context — Lollipop Plot

SYNE2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

MIM #612999

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.
Zuo X et al.·Nat Commun
2015
Common SYNE2 Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.
Liu N et al.·Circ Genom Precis Med
2024
EGFR and SYNE2 are associated with p21 expression and SYNE2 variants predict post-operative clinical outcomes in HBV-related hepatocellular carcinoma.
Han C et al.·Sci Rep
2016
Profibrotic Molecules Are Reduced in CRISPR-Edited Emery-Dreifuss Muscular Dystrophy Fibroblasts.
Cattin E et al.·Cells
2025
Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism.
Young N et al.·Genes (Basel)
2021Case report
Genomic characterization of vulvar squamous cell carcinoma.
Prieske K et al.·Gynecol Oncol
2020
Familial early-onset dementia with complex neuropathologic phenotype and genomic background.
Alexander J et al.·Neurobiol Aging
2016
A novel SYNE2 mutation identified by whole exome sequencing in a Korean family with Emery-Dreifuss muscular dystrophy.
Lee SJ et al.·Clin Chim Acta
2020Case report
Clinical Exome Gene Panel Analysis of a Cohort of Urothelial Bladder Cancer Patients from Sri Lanka.
Malalasekera A et al.·Asian Pac J Cancer Prev
2023Cohort
Genes Co-Expressed with ESR2 Influence Clinical Outcomes in Cancer Patients: TCGA Data Analysis.
Lipowicz JM et al.·Int J Mol Sci
2024Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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