# NM_001130965.3(SUN1):c.1749C>T (p.Ser583=)

https://sugi.bio/variant/sun1-p-ser583

## Summary

**SUN1 p.Ser583= (c.1749C>T)** is classified **Uncertain significance** in SUN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). Very rare (popmax 0.00329%, sas); Associated with Emery-Dreifuss muscular dystrophy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs780539401 · 1 submitter · 1 linked condition · very rare (popmax 0.00329%, sas)

## For patients & families {#patients}

This is a change in the SUN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Emery-Dreifuss muscular dystrophy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Emery-Dreifuss muscular dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pectus excavatum — Very frequent (99-80%)
- Reduced tendon reflexes — Very frequent (99-80%)
- Joint stiffness — Very frequent (99-80%)
- Myotonia — Very frequent (99-80%)
- Myopathy — Very frequent (99-80%)
- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Limb-girdle muscular dystrophy — Very frequent (99-80%)
- Sprengel anomaly — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006329/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SUN1](https://sugi.bio/atlas/gene/SUN1/) |
| Protein change (HGVS p.) | p.Ser583= |
| Coding change (HGVS c.) | c.1749C>T |
| MANE Select transcript | [NM_001130965](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130965) |
| dbSNP | [rs780539401](https://www.ncbi.nlm.nih.gov/snp/rs780539401/) |
| Variant type | single nucleotide variant |
| Location | chr7:860352-860352 (GRCh38) |
| ClinVar | [VCV662141](https://www.ncbi.nlm.nih.gov/clinvar/variation/662141/) |

**All HGVS expressions:** `NC_000007.13:g.899989C>T`, `NC_000007.14:g.860352C>T`, `NM_001130965.3:c.1749C>T`, `NM_001171944.2:c.1440C>T`, `NM_001367633.1:c.1749C>T`, `NM_001367634.1:c.1749C>T`, `NM_001367635.1:c.1398C>T`, `NM_001367636.1:c.1989C>T`, `NM_001367638.1:c.1857C>T`, `NM_001367639.1:c.1290C>T`, `NM_001367640.1:c.1929C>T`, `NM_001367641.1:c.2031C>T`, `NM_001367642.1:c.1734C>T`, `NM_001367643.1:c.1941C>T`, `NM_001367644.1:c.1680C>T`, `NM_001367645.1:c.1797C>T`, `NM_001367646.1:c.1878C>T`, `NM_001367647.1:c.1791C>T`, `NM_001367648.1:c.1611C>T`, `NM_001367649.1:c.1794C>T`, `NM_001367651.1:c.2163C>T`, `NM_001367653.1:c.1749C>T`, `NM_001367655.1:c.1959C>T`, `NM_001367658.1:c.1035C>T`, `NM_001367660.1:c.1566C>T`, `NM_001367662.1:c.1596C>T`, `NM_001367664.1:c.1860C>T`, `NM_001367665.1:c.1746C>T`, `NM_001367666.1:c.1992C>T`, `NM_001367667.1:c.1710C>T`, `NM_001367668.1:c.1791C>T`, `NM_001367669.1:c.1776C>T`, `NM_001367670.1:c.1599C>T`, `NM_001367671.1:c.1596C>T`, `NM_001367672.1:c.1716C>T`, `NM_001367673.1:c.1881C>T`, `NM_001367674.1:c.1947C>T`, `NM_001367675.1:c.1899C>T`, `NM_001367676.1:c.1932C>T`, `NM_001367677.1:c.2055C>T`, `NM_001367678.1:c.2139C>T`, `NM_001367679.1:c.1707C>T`, `NM_001367680.1:c.1683C>T`, `NM_001367681.1:c.1797C>T`, `NM_001367682.1:c.2031C>T`, `NM_001367683.1:c.1833C>T`, `NM_001367684.1:c.1908C>T`, `NM_001367685.1:c.1860C>T`, `NM_001367686.1:c.1581C>T`, `NM_001367688.1:c.1830C>T`, `NM_001367689.1:c.1710C>T`, `NM_001367690.1:c.2040C>T`, `NM_001367691.1:c.1989C>T`, `NM_001367692.1:c.2058C>T`, `NM_001367693.1:c.1944C>T`, `NM_001367694.1:c.1746C>T`, `NM_001367695.1:c.1671C>T`, `NM_001367696.1:c.1827C>T`, `NM_001367697.1:c.1944C>T`, `NM_001367698.1:c.2028C>T`, `NM_001367699.1:c.2139C>T`, `NM_001367700.1:c.1959C>T`, `NM_001367701.1:c.1650C>T`, `NM_001367702.1:c.1761C>T`, `NM_001367703.1:c.2142C>T`, `NM_001367704.1:c.1761C>T`, `NM_001367705.1:c.2142C>T`, `NM_001367706.1:c.1881C>T`, `NM_001367708.1:c.1182C>T`, `NM_025154.6:c.1500C>T`, `NR_160281.1:n.1797C>T`, `NR_160282.1:n.2160C>T`, `NR_160283.1:n.1901C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.68) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -10.842, GERP -6.26 — fast-evolving / accelerated position
- CADD: **PHRED 12.33**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.26**, acceptor gain **0.00**, donor gain **0.68**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.26**, acceptor gain **0.00**, donor gain **0.68**.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.12. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000474% · 3/91,084 in the highest group · 17/1,614,068 alleles overall — very rare (popmax 0.00329%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00329% | 30,361 |
| East Asian | 0.00223% | 44,884 |
| European (non-Finnish) | 0.0011% | 90,767 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SUN1** population constraint: LOEUF 0.712, pLI 1.432e-09, missense-Z 0.045491. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **583** lies in the 'sufficient for interaction with syne1 and syne2' region.

AlphaFold model confidence (whole protein): pLDDT 60.99, 18% of residues very-high.

**8 experimental structure(s)** (PDB): [6R15](https://www.rcsb.org/structure/6R15), [6R16](https://www.rcsb.org/structure/6R16), [6R2I](https://www.rcsb.org/structure/6R2I), [7E34](https://www.rcsb.org/structure/7E34), [7Z8Y](https://www.rcsb.org/structure/7Z8Y), [8AU0](https://www.rcsb.org/structure/8AU0).

## What this gene does {#gene-function}

*Describes the biological roles of SUN1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** SUN1's established molecular role includes identical protein binding. p.Ser583= falls in the sufficient for interaction with syne1 and syne2 region.


### Pathways affected {#pathways}

SUN1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding, cytoskeleton-nuclear membrane anchor activity.

**Biological process:** nuclear matrix anchoring at nuclear membrane.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-19.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-19 |

## Associated conditions {#conditions}

[Emery-Dreifuss muscular dystrophy](https://sugi.bio/atlas/disease/emery-dreifuss-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Emery-Dreifuss muscular dystrophy, Scapuloperoneal syndrome, X-linked (formerly), Humeroperoneal neuromuscular disease, (formerly).

## Similar variants {#similar}

Related SUN1 variant pages (same residue, condition, or type): [SUN1 p.Ser583Gly](/variant/sun1-p-ser583gly), [SUN1 p.Ala179Thr](/variant/sun1-p-ala179thr), [SUN1 p.Ala203Thr](/variant/sun1-p-ala203thr), [SUN1 p.Ala232Val](/variant/sun1-p-ala232val), [SUN1 p.Ala236Thr](/variant/sun1-p-ala236thr), [SUN1 p.Ala255Thr](/variant/sun1-p-ala255thr), [SUN1 p.Ala256Val](/variant/sun1-p-ala256val), [SUN1 p.Ala404Thr](/variant/sun1-p-ala404thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 662141). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*