# NM_015374.3(SUN2):c.524G>A (p.Arg175Gln)

https://sugi.bio/variant/sun2-p-arg175gln

## Summary

**SUN2 p.Arg175Gln (c.524G>A)** is classified **Uncertain significance** in SUN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-04). AlphaMissense: likely benign (0.091); Very rare (popmax 0.00446%, eas); Associated with Emery-Dreifuss muscular dystrophy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs901315537 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the SUN2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Arg175Gln |
| Coding change (HGVS c.) | c.524G>A |
| MANE Select transcript | [NM_015374](https://www.ncbi.nlm.nih.gov/nuccore/NM_015374) |
| dbSNP | [rs901315537](https://www.ncbi.nlm.nih.gov/snp/rs901315537/) |
| Variant type | single nucleotide variant |
| Location | chr22:38749856-38749856 (GRCh38) |
| ClinVar | [VCV3172123](https://www.ncbi.nlm.nih.gov/clinvar/variation/3172123/) |

**All HGVS expressions:** `NC_000022.10:g.39145861C>T`, `NC_000022.11:g.38749856C>T`, `NM_001199579.2:c.587G>A`, `NM_001199580.2:c.524G>A`, `NM_001394427.1:c.524G>A`, `NM_001394428.1:c.587G>A`, `NM_001394429.1:c.569G>A`, `NM_001394430.1:c.569G>A`, `NM_001394431.1:c.524G>A`, `NM_001394432.1:c.524G>A`, `NM_001394433.1:c.524G>A`, `NM_001394434.1:c.524G>A`, `NM_001394435.1:c.524G>A`, `NM_001394436.1:c.524G>A`, `NM_001394437.1:c.524G>A`, `NM_001394438.1:c.434G>A`, `NM_001394439.1:c.386G>A`, `NM_001394440.1:c.386G>A`, `NM_001394441.1:c.386G>A`, `NM_001394442.1:c.524G>A`, `NM_001394443.1:c.123-1073G>A`, `NM_001394444.1:c.524G>A`, `NM_001394445.1:c.524G>A`, `NM_015374.3:c.524G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.091)
- REVEL 0.098 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.312 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.35) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.636, GERP 2, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.6**. 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.*
- Regional missense constraint: **o/e 0.94** across the covering region of the MANE Select transcript (38,740,269–38,752,628), spanning 12,359 bp. Chi-square p 0.11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.12**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.12**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000277% · 2/44,834 in the highest group · 7/1,612,704 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,417 |
| Admixed American | 0.00167% | 59,832 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,422 |
| South Asian | 0.0011% | 90,912 |
| European (non-Finnish) | 0.00017% | 589,758 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Emery-Dreifuss muscular dystrophy, not specified, AllHighlyPenetrant, 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 3172123). 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.*