# NM_001130987.2(DYSF):c.2188C>G (p.Leu730Val)

https://sugi.bio/variant/dysf-p-leu730val

## Summary

**DYSF p.Leu730Val (c.2188C>G)** is classified **Uncertain significance** in DYSF (ClinVar, Single submitter, 2 submitters; last evaluated 2026-03-25). AlphaMissense: likely benign (0.1353); Very rare (popmax 8.6e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2B.

**At a glance:** Uncertain significance · review: Single submitter · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.6e-05%, nfe)

## For patients & families {#patients}

This is a change in the DYSF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2B.

*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 recessive |
| Age of onset (of this condition) | Adolescent, Adult |
| Prevalence | 1-9 / 1 000 000 (United Kingdom) |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DYSF is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Dysferlin-related limb-girdle muscular dystrophy R2** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Lower limb muscle weakness — Frequent (79-30%)
- Proximal muscle weakness in lower limbs — Frequent (79-30%)
- Reduced tendon reflexes — Occasional (29-5%)
- Cardiomegaly — Occasional (29-5%)
- Right ventricular hypertrophy — Occasional (29-5%)
- Pes cavus — Occasional (29-5%)
- Abnormal EKG — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008574/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYSF](https://sugi.bio/atlas/gene/DYSF/) |
| Protein change (HGVS p.) | p.Leu730Val |
| Coding change (HGVS c.) | c.2188C>G |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| Variant type | single nucleotide variant |
| Location | chr2:71556043-71556043 (GRCh38) |
| ClinVar | [VCV4067084](https://www.ncbi.nlm.nih.gov/clinvar/variation/4067084/) |

**All HGVS expressions:** `LRG_845:g.107421C>G`, `LRG_845t1:c.2134C>G`, `LRG_845t2:c.2188C>G`, `NC_000002.11:g.71783173C>G`, `NC_000002.12:g.71556043C>G`, `NG_008694.1:g.107421C>G`, `NM_001130455.2:c.2137C>G`, `NM_001130976.2:c.2092C>G`, `NM_001130977.2:c.2092C>G`, `NM_001130978.2:c.2134C>G`, `NM_001130979.2:c.2227C>G`, `NM_001130980.2:c.2185C>G`, `NM_001130981.2:c.2185C>G`, `NM_001130982.2:c.2230C>G`, `NM_001130983.2:c.2137C>G`, `NM_001130984.2:c.2095C>G`, `NM_001130985.2:c.2188C>G`, `NM_001130986.2:c.2095C>G`, `NM_001130987.2:c.2188C>G`, `NM_003494.4:c.2134C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1353)
- REVEL 0.165 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.884 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.897, GERP -0.719, phastCons 1 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **L712V** vs ClinVar **L730V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 21.1**. 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 0.82** across the covering region of the MANE Select transcript (71,551,716–71,569,909), spanning 18,193 bp. Chi-square p 4.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.24**. Largest is donor gain, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.6e-05%** (nfe) · 1/1,162,302 in the highest group · 1/1,577,302 alleles overall — very rare (popmax 8.6e-05%, nfe).

*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}

**DYSF** population constraint: LOEUF 0.836, pLI 3.6575e-52, missense-Z 1.3979. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **autosomal recessive limb-girdle muscular dystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **712** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 79.25, 28% of residues very-high.

**11 experimental structure(s)** (PDB): [4CAH](https://www.rcsb.org/structure/4CAH), [4CAI](https://www.rcsb.org/structure/4CAI), [4IHB](https://www.rcsb.org/structure/4IHB), [4IQH](https://www.rcsb.org/structure/4IQH), [7JOF](https://www.rcsb.org/structure/7JOF), [7K6B](https://www.rcsb.org/structure/7K6B) — incl. mutant structure 4IQH.

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

*Describes the biological roles of DYSF (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:** DYSF's established molecular role includes calcium ion binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | electronic |

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

**Molecular function:** calcium ion binding, phospholipid binding, calcium-dependent phospholipid binding.

**Biological process:** monocyte activation involved in immune response, macrophage activation involved in immune response, negative regulation of phagocytosis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-25.

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

**Submission history:** 2 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2025-01-20 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-03-25 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy type 2B](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2b/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy type 2B, not specified, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3, Limb-girdle muscular dystrophy, type 2B, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B), AllHighlyPenetrant.

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF c.1033+1G>A](/variant/dysf-c-1033-plus-1g-a), [DYSF c.1149+1G>A](/variant/dysf-c-1149-plus-1g-a), [DYSF c.1149+1G>C](/variant/dysf-c-1149-plus-1g-c), [DYSF c.1149+4A>G](/variant/dysf-c-1149-plus-4a-g), [DYSF c.1276+5G>A](/variant/dysf-c-1276-plus-5g-a), [DYSF c.1276+5G>C](/variant/dysf-c-1276-plus-5g-c), [DYSF c.1481-1G>A](/variant/dysf-c-1481-minus-1g-a), [DYSF c.1693-6T>A](/variant/dysf-c-1693-minus-6t-a).

### 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 4067084). 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.*