# NM_001130987.2(DYSF):c.1116C>G (p.Ser372Arg)

https://sugi.bio/variant/dysf-p-ser372arg

## Summary

**DYSF p.Ser372Arg (c.1116C>G)** is classified **Pathogenic** in DYSF (ClinVar, Expert panel, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.971); Very rare (popmax 0.000254%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs766891289 · 8 submitters · 4 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the DYSF gene that is considered disease-causing, submitted by 8 submitters, and is linked to autosomal recessive limb-girdle 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019825/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.Ser372Arg |
| Coding change (HGVS c.) | c.1116C>G |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs766891289](https://www.ncbi.nlm.nih.gov/snp/rs766891289/) |
| Variant type | single nucleotide variant |
| Location | chr2:71520871-71520871 (GRCh38) |
| ClinVar | [VCV288183](https://www.ncbi.nlm.nih.gov/clinvar/variation/288183/) |

**All HGVS expressions:** `LRG_845:g.72249C>G`, `LRG_845t1:c.1020C>G`, `LRG_845t2:c.1116C>G`, `NC_000002.11:g.71748001C>G`, `NC_000002.12:g.71520871C>G`, `NG_008694.1:g.72249C>G`, `NM_001130455.2:c.1023C>G`, `NM_001130976.2:c.1020C>G`, `NM_001130977.2:c.1020C>G`, `NM_001130978.2:c.1020C>G`, `NM_001130979.2:c.1113C>G`, `NM_001130980.2:c.1113C>G`, `NM_001130981.2:c.1113C>G`, `NM_001130982.2:c.1116C>G`, `NM_001130983.2:c.1023C>G`, `NM_001130984.2:c.1023C>G`, `NM_001130985.2:c.1116C>G`, `NM_001130986.2:c.1023C>G`, `NM_001130987.2:c.1116C>G`, `NM_003494.4:c.1020C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.971) — concordant with the pathogenic call
- REVEL 0.695 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.655 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 0.104, GERP -2.02, phastCons 0.736 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S340R** vs ClinVar **S372R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in DYSF (of 12,318 modeled).
- CADD: **PHRED 20.2**. 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 1.02** across the covering region of the MANE Select transcript (71,466,843–71,551,715), spanning 84,872 bp. Chi-square p 0.54. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,180,012 in the highest group · 3/1,461,826 alleles overall — very rare (popmax 0.000254%, 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 **372** lies in a turn; the c2 3 domain.

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. p.Ser372Arg falls in the c2 3 domain.


### 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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (4 Likely pathogenic, 3 Pathogenic, 1 Uncertain significance).

**Submission history:** 8 submissions (2016–2026); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Limb Girdle Muscular Dystrophy VCEP (autosomal recessive limb-girdle muscular dystrophy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS3_Moderate`, `PP4_Strong`, `PS1`, `PM3`.
*Considered but not met:* `PP3`, `BP7`, `PM5`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_003494.4: c.1020C>G variant in DYSF, which is also known as NM_001130987.2: c.1116C>G p.(Ser372Arg), is a missense variant predicted to cause substitution of serine by arginine at amino acid 340, p.(Ser340Arg). This variant has been reported in at least seven patients with features consistent with LGMD (PMID: 33927379, 30564623, 19730931; ClinVar SCV002073234.1; Jain Foundation Dysferlin Registry internal data communication; LOVD DYSF_000465), including in a homozygous state without reported familial consanguinity in at least four unrelated patients (1.0 pt, PMID: 19730931, 33927379; ClinVar SCV002073234.1; Jain Foundation Dysferlin Registry internal data communication) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF allele had both a clinical diagnosis of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 33927379, LOVD Individual #00327530; PP4_Strong). The filtering allele frequency for this variant is 0.000006571 in gnomAD v4.1.0 (the upper bound of the 95% confidence interval of 3/1180012 European (non-Finnish) chromosomes), which is less than the threshold of 0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.695, which is below the LGMD VCEP threshold of ≥0.70 for PP3 (criterion not met), but immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Ser340Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate). Another nucleotide change at the same position resulting in the same amino acid change, NM_003494.4: c.1020C>A p.(Ser340Arg), is classified as pathogenic by the LGMD VCEP (PS1). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 02/02/2026): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PS1.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2026-02-02 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/db7a092b-9a9d-438f-8cd6-f6a7297ced14).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-30 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-04-04 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-05-23 |
| Kariminejad - Najmabadi Pathology & Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-15 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-30 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2026-02-02 |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-31 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy/), [autosomal recessive limb-girdle muscular dystrophy type 2B](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2b/), [neuromuscular disease caused by qualitative or quantitative defects of dysferlin](https://sugi.bio/atlas/disease/neuromuscular-disease-caused-by-qualitative-or-quantitative-defects-of-dysferlin/), [Miyoshi muscular dystrophy 1](https://sugi.bio/atlas/disease/miyoshi-muscular-dystrophy-1/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, not provided, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, Autosomal recessive limb-girdle muscular dystrophy type 2B, Miyoshi muscular dystrophy 1, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, Limb-girdle muscular dystrophy, type 2B, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B), MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3, Dysferlinopathy.

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Ser372=](/variant/dysf-p-ser372), [DYSF c.1003-3C>A](/variant/dysf-c-1003-minus-3c-a), [DYSF c.1033+1G>A](/variant/dysf-c-1033-plus-1g-a), [DYSF c.1033+4A>T](/variant/dysf-c-1033-plus-4a-t), [DYSF c.1033+5G>A](/variant/dysf-c-1033-plus-5g-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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 288183). 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.*