# NM_001130987.2(DYSF):c.6155C>G (p.Pro2052Arg)

https://sugi.bio/variant/dysf-p-pro2052arg

## Summary

**DYSF p.Pro2052Arg (c.6155C>G)** is classified **Likely pathogenic** in DYSF (ClinVar, Expert panel, 3 submitters; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.9309); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs886044643 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DYSF gene that is considered likely disease-causing, submitted by 3 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.Pro2052Arg |
| Coding change (HGVS c.) | c.6155C>G |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs886044643](https://www.ncbi.nlm.nih.gov/snp/rs886044643/) |
| Variant type | single nucleotide variant |
| Location | chr2:71681092-71681092 (GRCh38) |
| ClinVar | [VCV291078](https://www.ncbi.nlm.nih.gov/clinvar/variation/291078/) |

**All HGVS expressions:** `LRG_845:g.232470C>G`, `LRG_845t1:c.6038C>G`, `LRG_845t2:c.6155C>G`, `NC_000002.11:g.71908222C>G`, `NC_000002.12:g.71681092C>G`, `NG_008694.1:g.232470C>G`, `NM_001130455.2:c.6041C>G`, `NM_001130976.2:c.5996C>G`, `NM_001130977.2:c.6059C>G`, `NM_001130978.2:c.6101C>G`, `NM_001130979.2:c.6131C>G`, `NM_001130980.2:c.6089C>G`, `NM_001130981.2:c.6152C>G`, `NM_001130982.2:c.6134C>G`, `NM_001130983.2:c.6104C>G`, `NM_001130984.2:c.6062C>G`, `NM_001130985.2:c.6092C>G`, `NM_001130986.2:c.5999C>G`, `NM_001130987.2:c.6155C>G`, `NM_003494.3:c.6038C>G`, `NM_003494.4:c.6038C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9309) — concordant with the pathogenic call
- REVEL 0.834 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.75 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.31) — consistent with the pathogenic call
- Conservation: phyloP 7.633, GERP 2.14, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P2013R** vs ClinVar **P2052R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 27.8**. 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 0.97** across the covering region of the MANE Select transcript (71,569,910–71,686,489), spanning 116,579 bp. Chi-square p 0.28. 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 **0.01**, acceptor gain **0.00**, donor gain **0.31**. 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.*
- Pangolin: Δ**0.20** (gain), gain 0.20 / loss 0.05. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-06-10.

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

**Submission history:** 3 submissions (2016–2025); classifications have differed over time.

**ClinGen expert panel:** Likely 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):** `PM3_Supporting`, `PM2_Supporting`, `PP4_Strong`, `PP3`.
*Considered but not met:* `PM5`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_003494.4: c.6038C>G variant in DYSF, which is also known as NM_001130987.2: c.6155C>G p.(Pro2052Arg), is a missense variant predicted to cause substitution of proline by arginine at amino acid 2013, p.(Pro2013Arg).  This variant has been reported in unknown phase with a pathogenic variant in at least one individual with LGMD (NM_003494.4: c.3137G>A p.(Arg1064His), 0.5 pts, PMID: 36983702, 30564623;  LOVD Individual #00221252) (PM3_Supporting). This individual displayed progressive limb girdle muscle weakness and disease range dysferlin expression by blood monocyte assay, which is highly specific for DYSF-related LGMD (PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function.  In addition, SpliceAI gives a score of 0.31 for donor gain. (PP3). In summary, this variant meets the criteria to be classified as Likely 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 1.0.0; 06/10/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PP3.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-06-10 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/269e144b-4131-4ccc-ba25-b60cddc1be71).*
*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 |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-09-13 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2025-06-10 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-03-14 |

## 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/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, not provided, Autosomal recessive limb-girdle muscular dystrophy type 2B, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3, Limb-girdle muscular dystrophy, type 2B, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B), MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, none provided.

## Same-residue context {#hotspot}

Residue **2052** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DYSF p.Pro2052fs](/variant/dysf-p-pro2052fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Pro2052Ala](/variant/dysf-p-pro2052ala), [DYSF p.Pro2052Leu](/variant/dysf-p-pro2052leu), [DYSF p.Pro2052=](/variant/dysf-p-pro2052), [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).

### 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 291078). 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.*