# NM_015374.3(SUN2):c.633G>A (p.Lys211=)

https://sugi.bio/variant/sun2-p-lys211

## Summary

**SUN2 p.Lys211= (c.633G>A)** is classified **Likely benign** in SUN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-03). Very rare (popmax 0.00833%, amr); Associated with Emery-Dreifuss muscular dystrophy.

**At a glance:** Likely benign · review: Single submitter · rsID rs1347064197 · 1 submitter · 1 linked condition · very rare (popmax 0.00833%, amr)

## For patients & families {#patients}

This is a change in the SUN2 gene that is classified as likely benign — not considered disease-causing, 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 | [SUN2](https://sugi.bio/atlas/gene/SUN2/) |
| Protein change (HGVS p.) | p.Lys211= |
| Coding change (HGVS c.) | c.633G>A |
| MANE Select transcript | [NM_015374](https://www.ncbi.nlm.nih.gov/nuccore/NM_015374) |
| dbSNP | [rs1347064197](https://www.ncbi.nlm.nih.gov/snp/rs1347064197/) |
| Variant type | single nucleotide variant |
| Location | chr22:38748765-38748765 (GRCh38) |
| ClinVar | [VCV1155595](https://www.ncbi.nlm.nih.gov/clinvar/variation/1155595/) |

**All HGVS expressions:** `NC_000022.10:g.39144770C>T`, `NC_000022.11:g.38748765C>T`, `NM_001199579.2:c.696G>A`, `NM_001199580.2:c.633G>A`, `NM_015374.3:c.633G>A`

## 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 **acceptor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.147, GERP 2.16, phastCons 0.961 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.81**. 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 **0.20**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.20**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.22** (loss), gain 0.00 / loss 0.22. 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 **0.00833%** (amr) · FAF95 0.00323% · FAF99 0.00206% · 5/60,034 in the highest group · 7/1,614,240 alleles overall — very rare (popmax 0.00833%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00833% | 12,007 |
| European (non-Finnish) | 0.000169% | 590,019 |

*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}

**SUN2** population constraint: LOEUF 0.756, pLI 1.156e-11, missense-Z 1.6318. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.48, 27% of residues very-high.

**9 experimental structure(s)** (PDB): [3UNP](https://www.rcsb.org/structure/3UNP), [4DXR](https://www.rcsb.org/structure/4DXR), [4DXS](https://www.rcsb.org/structure/4DXS), [4DXT](https://www.rcsb.org/structure/4DXT), [4FI9](https://www.rcsb.org/structure/4FI9), [6WMD](https://www.rcsb.org/structure/6WMD).

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

*Describes the biological roles of SUN2 (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:** SUN2's established molecular role includes lamin binding. In Reactome, SUN2 is annotated in disease pathway(s) including **Dengue Virus Genome Translation and Replication**.

**Disease mechanism (Reactome):** SUN2 loss or alteration is curated in [Dengue Virus Genome Translation and Replication](https://reactome.org/content/detail/R-HSA-9918487).

### Pathways affected {#pathways}

SUN2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus Genome Translation and Replication](https://reactome.org/content/detail/R-HSA-9918487) | other |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | other |

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

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

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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-03.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-03 |

## 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 SUN2 variant pages (same residue, condition, or type): [SUN2 p.Ala158Thr](/variant/sun2-p-ala158thr), [SUN2 p.Ala251Val](/variant/sun2-p-ala251val), [SUN2 p.Ala508Val](/variant/sun2-p-ala508val), [SUN2 p.Ala56Val](/variant/sun2-p-ala56val), [SUN2 p.Arg100Gln](/variant/sun2-p-arg100gln), [SUN2 p.Arg102Gln](/variant/sun2-p-arg102gln), [SUN2 p.Arg102Trp](/variant/sun2-p-arg102trp), [SUN2 p.Arg104Lys](/variant/sun2-p-arg104lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1155595). 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.*