# NM_001130987.2(DYSF):c.6180C>T (p.Pro2060=)

https://sugi.bio/variant/dysf-p-pro2060

## Summary

**DYSF p.Pro2060= (c.6180C>T)** is classified **Conflicting classifications of pathogenicity** in DYSF (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-21). Rare (popmax 0.453%, afr); Associated with neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147263499 · 9 submitters · 3 linked conditions · rare (popmax 0.453%, afr)

## For patients & families {#patients}

This is a change in the DYSF gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to neuromuscular disease caused by qualitative or quantitative defects of dysferlin.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002003/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.Pro2060= |
| Coding change (HGVS c.) | c.6180C>T |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs147263499](https://www.ncbi.nlm.nih.gov/snp/rs147263499/) |
| Variant type | single nucleotide variant |
| Location | chr2:71682536-71682536 (GRCh38) |
| ClinVar | [VCV281355](https://www.ncbi.nlm.nih.gov/clinvar/variation/281355/) |

**All HGVS expressions:** `LRG_845:g.233914C>T`, `LRG_845t1:c.6063C>T`, `LRG_845t2:c.6180C>T`, `NC_000002.11:g.71909666C>T`, `NC_000002.12:g.71682536C>T`, `NG_008694.1:g.233914C>T`, `NM_001130455.2:c.6066C>T`, `NM_001130976.2:c.6021C>T`, `NM_001130977.2:c.6084C>T`, `NM_001130978.2:c.6126C>T`, `NM_001130979.2:c.6156C>T`, `NM_001130980.2:c.6114C>T`, `NM_001130981.2:c.6177C>T`, `NM_001130982.2:c.6159C>T`, `NM_001130983.2:c.6129C>T`, `NM_001130984.2:c.6087C>T`, `NM_001130985.2:c.6117C>T`, `NM_001130986.2:c.6024C>T`, `NM_001130987.2:c.6180C>T`, `NM_003494.4:c.6063C>T`

## 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 gain** (Δ 0.58) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -10.799, GERP -3.89 — fast-evolving / accelerated position
- CADD: **PHRED 15.88**. 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 **0.02**, donor loss **0.00**, acceptor gain **0.58**, donor gain **0.00**. Largest is acceptor gain, 37 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**0.29** (gain), gain 0.29 / loss 0.09. 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 **0.453%** (afr) · FAF95 0.414% · FAF99 0.398% · 340/74,998 in the highest group · 685/1,614,056 alleles overall — rare (popmax 0.453%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.453% | 221 |
| Middle Eastern | 0.148% | 674 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.115% | 871 |
| Remaining individuals (not grpmax-eligible) | 0.0768% | 1,302 |
| East Asian | 0.0602% | 1,661 |
| South Asian | 0.034% | 2,938 |
| Admixed American | 0.0333% | 3,000 |
| European (non-Finnish) | 0.0148% | 6,743 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,034 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-21.

**Submitter consensus:** conflicting (4 Benign, 4 Likely benign, 1 Uncertain significance).

**Submission history:** 9 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2017-04-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-13 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2019-04-27 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-18 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-07-10 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-10-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-12 |

## Associated conditions {#conditions}

[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/), [autosomal recessive limb-girdle muscular dystrophy type 2B](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2b/), [Miyoshi muscular dystrophy 1](https://sugi.bio/atlas/disease/miyoshi-muscular-dystrophy-1/).

**Reported phenotype names (ClinVar):** Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, not specified, not provided, Miyoshi muscular dystrophy 1, Autosomal recessive limb-girdle muscular dystrophy type 2B, AllHighlyPenetrant, none provided, Dysferlinopathy, Qualitative or quantitative defects of dysferlin, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2.

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF p.Pro2060Leu](/variant/dysf-p-pro2060leu), [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.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).

### 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 281355). 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.*